From: kristoff@NET.BIO.NET (Dave Kristofferson)
Newsgroups: bionet.sci-resources
Subject: NIH Guide, vol. 21, no. 45, pt. 4, 18 December 1992
Date: 17 Dec 92 02:46:51 GMT
Distribution: bionet


$$XID RFA AI9307 AI-93-07 P1O1 *****************************************

MECHANISMS OF PERIPHERAL IMMUNOLOGICAL TOLERANCE AND ANERGY

NIH GUIDE, Volume 21, Number 45, December 18, 1992

RFA:  AI-93-07

P.T. 34; K.W. 0710070, 0715015

National Institute of Allergy and Infectious Diseases

Letter of Intent Date:  January 15, 1993
Application Receipt Date:  March 25, 1993

PURPOSE

The Division of Allergy, Immunology and Transplantation (DAIT) of the
National Institute of Allergy and Infectious Diseases (NIAID) invites
applications for studies dealing with the mechanisms of peripheral
immunological tolerance and anergy.  Improved knowledge of peripheral
tolerance and anergy is likely to open new avenues to:  treatment or
prevention of a variety of autoimmune and allergic disorders,
moderating organ and bone marrow graft rejection, and vaccination
against infectious organisms.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This Request
for Applications (RFA), Mechanisms of Peripheral Immunological
Tolerance and Anergy, is related to the priority areas of diabetes
and chronic disabling diseases, and to immunization and infectious
diseases.  Potential applicants may obtain a copy of "Healthy People
2000" (Full Report:  Stock No. 017-001-00474-0) or "Healthy People
2000"  (Summary Report:  Stock No. 017-001-00473-1) through the
Superintendent of Documents, Government Printing Office, Washington,
DC 20402-9325 (telephone 202-782-3238).

ELIGIBILITY REQUIREMENTS

Only domestic organizations are eligible to apply.  Applications may
be submitted by domestic for-profit and non-profit organizations,
public and private, such as universities, colleges, hospitals,
laboratories, units of State and local governments, and eligible
agencies of the Federal government.  The NIAID encourages the
participation of minorities and women, either as the Program Director
or as project leaders of the component research projects of the
application.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) Program
Project grant (P01).  A P01 is awarded to an institution on behalf of
a Program Director for the support of a broadly based,
multidisciplinary, long-term research program with a specific major
goal or central theme.  A P01 generally involves the organized
efforts of a group of investigators who conduct research projects
related to the overall program goal.  The grant may provide support
for the projects and for certain central resources shared by
individuals in the P01 if sharing facilitates the total research
effort.  Each project supported under a P01 is expected to contribute
to and be directly related to the central theme of the program.  The
projects, each under the direction of a Project Leader, must
demonstrate an essential element of unity and interdependence.

The application should clearly explain how the projected
multidisciplinary integrated program can be expected to accomplish
the stated goal more efficiently and effectively than could a series
of independent, individual grant-supported studies.

Designation of a Principal Investigator as Program Director must be
based upon accomplishment and experience as a scientist, the ability
to assume both the leadership of the research group and the
responsibility for scientific, professional, and administrative
functions, and the commitment of a significant amount of his/her time
to the project.  Each research project in the program should have a
designated Project Leader with a demonstrable record of
accomplishment in immunology or one of the basic science disciplines
or clinical specialties relevant to the particular subject of
investigation.  However, the NIAID encourages the designation as
Project Leader of one junior investigator whose scientifically
meritorious project is an integral part of the overall program and
whose work would be closely related to that of one or more senior
scientists of the P01.

The total project period for applications submitted in response to
this RFA may not exceed five years.  At this time, the NIAID is
administratively limiting the duration of such grants to four years;
this administrative limitation may change in the future.  The budget
of the P01 application should not exceed $500,000 total direct costs
in the first year and no more than four percent annual inflationary
increases for future years.  Applications with an annual budget
request in excess of this amount will require written approval by
senior NIAID officials via the program officer for acceptance of the
application for processing.

FUNDS AVAILABLE

The estimated total funds (direct and indirect costs) available for
the first year of support for this RFA will be $1,500,000.  In Fiscal
Year 1993, the NIAID plans to award at least two program project
grants submitted in response to this RFA and, depending on
availability of funds and scientific merit, possibly more than two.
PHS policies governing grants administration and management will
apply.  This level of support is dependent on the receipt of a
sufficient number of applications of high scientific merit.  Although
this program is provided for in the financial plans of the NIAID,
awards pursuant to this RFA are contingent upon the availability of
funds for this purpose.  Funding beyond the first and subsequent
years of the grant will be contingent upon satisfactory progress
during the preceding years and availability of funds.

RESEARCH OBJECTIVES

Background

Tolerance and anergy may be imposed at any of several levels within
the immune system and, while the precise mechanisms may vary,
together these levels probably constitute a hierarchy that is
designed to prevent normal physiological reactions against self from
leading to autoimmune disorders. Thus, tolerance may arise from
clonal deletion of potentially autoaggressive T cells within the
thymus ("ignorance of self").  Alternatively, prospective T cells may
be rendered nonfunctional ("anergic") within the thymus and
subsequently be exported without dying.  Similarly, extrathymic T
cells may be eliminated by programmed cell death or rendered anergic,
although still viable.  Both B and T lymphocytes are susceptible to
the induction of tolerance and anergy.  Because central T cell
nonresponsiveness appears at present to be receiving the most
attention, this RFA is intended to promote research on the mechanisms
leading to clonal deletion and functional inactivation of peripheral
lymphocytes, both B and T.

Research Objectives and Scope

The goal of this program is to gain a comprehensive understanding of
the nature of peripheral tolerance and anergy:  what they are, how
they are induced, and the biochemical and molecular genetic events
involved in inducing and maintaining them.  Studies that involve
humans and human tissues and cells, are especially encouraged.  The
following are some examples of the questions about T lymphocytes that
need to be addressed:

o  What are the elements (e.g., types of interacting cells, surface
molecules, cytokines) and mechanisms involved in T cell tolerance and
anergy that operate extrathymically?

o  Do the mechanisms that lead to tolerance and anergy differ
depending on the tolerizing/anergizing stimulus?  For example, would
the mechanisms differ if a convential antigen or a super-antigen were
involved or if the stimulus were a free peptide compared to a Class
II-peptide complex?

o  What roles are played by the Ti-CD3 complex or by CD4 and CD8
accessory molecules in the induction of T cell tolerance?

o  Are CD4+ and CD8+ T cells distinguishable in their susceptibility
to the induction of tolerance and anergy?

o  What are the different roles played by TH1 and TH2 cells and the
spectra of cytokines that they secrete in the induction and
maintenance of tolerance and anergy?

The following are some examples of the questions about B lymphocytes
that need to be addressed:

o  What is the importance of the density, distribution, affinity and
isotype of membrane-bound antibody molecules?

o  Is B-cell anergy associated with the absence of stimuli/signals
that would otherwise lead to B-cell activation and, if so, what is
the nature of such stimuli?

o  What is the importance of the differentiative status of B cells in
terms of the induction of tolerance and anergy?

The prospects of important clinical applications calls for a
concerted effort to acquire better understanding of these phenomena.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy requires that applicants for NIH clinical research grants
and cooperative agreements include minorities and women in study
populations so that research findings can be of benefit to all
persons at risk of the disease, disorder or condition under study;
special emphasis must be placed on the need for inclusion of
minorities and women in studies of diseases, disorders and conditions
which disproportionately affect them.  This policy is intended to
apply to males and females of all ages.  If women or minorities are
excluded or inadequately represented in clinical research,
particularly in proposed population-based studies, a clear compelling
rationale MUST be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group, together with a rationale
for its choice.  In addition, gender and racial/ethnic issues should
be addressed in developing a research design and sample size
appropriate for the scientific objectives of the study.  This
information should be included in the form PHS 398 in items 1-4 of
the Research Plan AND summarized in item 5, Human Subjects.

Applicants are urged to assess carefully the feasibility of including
the broadest possible representation of minority groups.  However,
NIH recognizes that it may not be feasible or appropriate in all
research projects to include representation of the full array of
United States racial/ethnic minority populations [i.e., Native
Americans (including American Indians or Alaskan Natives),
Asian/Pacific Islanders, Blacks, Hispanics].  The rationale for
studies on single minority population groups should be provided.

For the purpose of this policy, clinical research includes human
biomedical and behavioral studies of etiology, epidemiology, (and
preventive strategies), diagnosis, or treatment of diseases,
disorders or conditions, including but not limited to, clinical
trials.

The usual NIH policies concerning research on human subjects also
apply. Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
clinical samples which may be coded for use by the applicant but
could be identified by another source are not excluded.  Every effort
should be made and documented to include human tissues from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

If the required information is not contained within the application,
the application will be returned.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the
selected study population is inadequate, it will be considered a
scientific weakness or deficiency in the study design and will be
reflected in assigning the priority score to the application.

All applications for clinical research submitted to NIH are required
to address these policies.  NIH funding components will not award
grants or cooperative agreements that do not comply with these
policies.

LETTER OF INTENT

Prospective applicants are asked to submit, by January 15, 1993, a
letter of intent that includes a descriptive title of the overall
proposed research, the name, address and telephone number of the
Principal Investigator (Program Director), the names of key
investigators, their institution(s), and the number and title of this
RFA.  Although the letter of intent is not required, is not binding,
does not commit the sender to submit an application, and does not
enter into the review of subsequent applications, the information
that it contains allows NIAID staff to estimate the potential review
workload and to avoid conflict of interest in the review.  The letter
of intent is to  be sent to Dr. Mark Rohrbaugh at the address listed
under INQUIRIES.

APPLICATION PROCEDURES

Applications are to be submitted on the standard research grant
application form PHS 398 (rev. 09/91).  Item 2a on the face page of
the application must be marked "yes" and the RFA number and the words
MECHANISMS OF PERIPHERAL IMMUNOLOGICAL TOLERANCE AND ANERGY must be
typed in.

These application forms may be obtained from the institution's office
of sponsored research and from the Office of Grants Inquiries,
Division of Research Grants, National Institutes of Health, 5333
Westbard Avenue, Room 449, Bethesda, Maryland 20892, telephone (301)
496-7441.

It is highly recommended that the Chief of the Basic Immunology
Branch or the Chief of the Immunoregulation Section be contacted in
the early stages of preparation of the application.

Applications must be received by March 25, 1993.  Applications that
are not received by the receipt date or that do not conform to the
instructions contained in PHS 398 (rev. 09/91) application kit, will
be judged non-responsive and will be returned to the applicant.

The RFA label available in the application form must be affixed to
the bottom of the face page.  Failure to use this label could result
in delayed processing of the application such that it may not reach
the review committee in time for review.

Submit a signed, typewritten original of the application, including
the checklist, and three signed, exact, single-sided photocopies, in
one package to:

Application Receipt Office
Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

At the time of submission, two additional exact copies of the
application must also be sent to Dr. Mark Rohrbaugh at the address
under INQUIRIES.

REVIEW CONSIDERATIONS

General review considerations are outlined in the NIAID Information
Brochure on Program Project and Center Grants, which contains special
instructions for preparing multiproject applications for Program
Projects.  It includes REVIEW PROCEDURES and REVIEW CRITERIA for
multicomponent, interdisciplinary projects and other important
information.  This Information Brochure and the RFA will be sent to
applicants upon request.

Upon receipt, applications will be reviewed for completeness by the
Division of Research Grants (DRG) and for responsiveness by NIAID
staff; those judged to be incomplete or non-responsive will be
returned to the applicant without review.

Those applications that are complete and responsive may be subjected
to a triage by an NIAID peer review group before or during the
scientific review meeting to determine their scientific merit
relative to other applications received in response to this RFA.  The
NIAID will withdraw from competition those applications judged to be
non-competitive for award and will notify the applicant and
institutional business officials.

Those applications judged by the reviewers to be competitive for
award will be further reviewed for scientific and technical merit by
a review committee convened by the Division of Extramural Activities,
NIAID.  The second level of review will be provided by the National
Advisory Allergy and Infectious Diseases Council.

Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center for Research
Resources may wish to identify the GCRC as a resource for conducting
the proposed research.  If so, a letter of agreement from either the
GCRC Program Director or the Principal Investigator of the GCRC must
be included with the application.

Review Criteria

The general criteria are those review criteria for large,
multicomponent, interdisciplinary program projects as outlined in the
NIAID Brochure on Project Project and Center Grants.

AWARD CRITERIA

Funding decisions will be made on the basis of scientific and
technical merit as determined by peer review, program needs and
balance, and the availability of funds.

INQUIRIES

Written and telephone inquiries concerning this RFA are encouraged.
The opportunity to clarify any issues or questions from potential
applicants is welcome.

Direct inquiries about the RFA and programmatic issues to:

Joseph F. Albright, Ph.D. or M. Michele Hogan, Ph.D.
Division of Allergy, Immunology and Transplantation
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4A22
Bethesda, MD  20892
Telephone:  (301) 496-7551
FAX:  (301) 402-0175

Direct inquiries regarding review issues, and address the letter of
intent to:

Mark Rohrbaugh, Ph.E., Scientific Review Administrator
Microbiology and Immunology Review Section
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C22
Bethesda, MD  20892
Telephone:  (301) 496-8424
FAX:  (301) 402-2638

Direct inquiries regarding fiscal matters to:

Mr. Jeffrey Carow
Chief, Immunology Grants Management Section
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B92
Bethesda, MD  20892
Telephone:  (301) 496-7075

The mailing address for sending applications to NIAID staff in the
Solar
Building is the central mailing address for NIH.  Applicants who use
express
mail or a courier service are advised to follow the carrier's
requirements for
showing a street address.  The address for the Solar Building is:

6003 Executive Boulevard
Rockville, MD  20852

Schedule

Letter of Intent Date:     January 15, 1993
Application Receipt Date:  March 25, 1993
Scientific Review Date:    June 1993
Advisory Council Date:     September 1993
Earliest Award Date:       September 1993

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance, No. 93.855 - Immunology, Allergy and Transplantation
Research.  Awards will be made under the authority of the Public
Health Service Act, Title III, Section 301 (Public Law 78-410, as
amended; 42 USC 241) and administered under PHS grants policies and
Federal Regulations 42 CFR Part 74.  This program is not subject to
the intergovernmental review requirements of Executive Order 12372 or
Health Systems Agency review.


$$XID RFA DK9321 DK-93-21 P1O1 *****************************************

UROLOGY RESEARCH CENTERS

NIH GUIDE, Volume 21, Number 45, December 18, 1992

RFA:  DK-93-21

P.T. 04; K.W. 0785220, 1002004, 1002008, 0710070, 1002019, 0710030

National Institute of Diabetes and Digestive and Kidney Diseases
National Cancer Institute

Letter of Intent Receipt Date:  March 8, 1993
Application Receipt Date:  April 9, 1993

PURPOSE

This Request for Applications (RFA) invites investigators to submit
research applications for the George M. O'Brien Research Centers
Program.  The emphases for this program are threefold:  (1) to
attract new scientific expertise into the study of the basic
mechanisms of urological diseases and disorders; (2) to encourage
multidisciplinary research focused on the causes of these diseases
and disorders; and (3) to extend the development of innovative
clinical and epidemiologic studies of the causes, therapy and
possible prevention of urological diseases and disorders.  In
approaching the study of these disease processes, it is anticipated
that extensive collaboration will be required between individuals in
the clinical and basic sciences, including for example investigators
with training and expertise in cell biology, molecular biology,
immunology, genetics, epidemiology, biochemistry, physiology, and
pathology.  It is the express intent of the announcement to attract
new investigators not currently active in this field and to explore
new basic areas that may have clinical research applications.
Individual institutions with both basic and clinical research
capabilities are invited to apply.  Interinstitutional collaborative
research arrangements are also appropriate and encouraged.
Coordination for such arrangements must be evident and clearly
meaningful and appropriate for the research proposed.

The National Cancer Institute (NCI) plans to provide support for this
program in the area of prostate cancer.  Studies to be supported
include the full range from laboratory to clinical investigations
encompassing biology, etiology, detection, diagnosis, treatment,
prevention and control.  Of particular interest is multidisciplinary
research that links basic research to applied settings involving
patients and populations.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This RFA,
Urology Research Centers, is related to the area of diabetes and
other chronic disabling conditions.  Potential applicants may obtain
a copy of "Healthy People 2000" (Full Report:  Stock No.
017-001-00474-0) or "Healthy People 2000" (Summary Report:  Stock No.
017-001-00473-1) through the Superintendent of Documents, Government
Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic for-profit and non-profit
organizations, public and private, such as universities, colleges,
hospitals, laboratories, units of State and local governments, and
eligible agencies of the Federal government.  Foreign institutions
are not eligible to apply.  Minority individuals and women are
encouraged to submit as principal investigators.

MECHANISM OF SUPPORT

Support of this program will be through the National Institutes of
Health (NIH) specialized center (P50) award.  Responsibility for the
planning, direction, and execution of the proposed project will be
solely that of the applicant.  Except as otherwise stated in this
announcement, awards will be administered under PHS grants policy as
stated in the PHS Grants Policy Statement.

FUNDS AVAILABLE

The National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK) and the NCI expect to jointly award up to two center grants
(P50) in fiscal year 1993 for research into urologic disorders.  The
anticipated awards are for five years and are contingent upon the
availability of appropriated funds.  The total amount of available
funds to support this program is anticipated to be no more than $1.5
million per year.  No applicant may request more than $750,000 in
total costs (including both direct and indirect costs) in the initial
budget period.  A standard escalation factor may be used for
subsequent budget periods.  The award date for these grants will be
September 30, 1993.

RESEARCH OBJECTIVES

Urologic diseases and disorders place a substantial burden on
individuals and on society in the United States.  Urinary tract
infections had a direct hospital and physican cost of over $4 billion
in 1990.  Benign prostatic hyperplasia (over $2 billion), stone
disease (over $1 billion), and bladder disorders (over $1 billion)
are disorders whose costs each exceed $1 billion annually.  These
diseases and disorders threaten the health, well-being, and longevity
of millions of Americans.  Although considerable progress has been
made in understanding the basic physiology and pathophysiology of the
normal urologic systems, there has been only limited progress in
unraveling the mechanisms of those processes that lead to progressive
deterioration in the function of these systems.  Nevertheless, major
progress has been made in the management of their clinical
consequences.  For example, the clinical management of benign
prostatic hyperplasia has improved over the past several years.
Unfortunately, these scientific and medical advances have not led to
the means to prevent or reverse the consequences of these diseases
and disorders; moreover their incidence is steadily increasing.  The
proposed multidisciplinary research centers should help to provide an
environment for investigators to apply the necessary and appropriate
expertise to topical areas of research related to the pathogenesis of
urologic diseases such as: immunologically mediated diseases;
diabetes mellitus and other endocrine and metabolic disorders;
genetic abnormalities; bladder physiology and pathophysiology; and
developmental and obstructive disorders.

Prostate cancer is the most common cancer in U.S. males and is the
second leading cause of cancer death in men.  Mortality due to
prostate cancer is two-fold higher in U.S black men than in U.S.
white men.  Costs attributable to this disease exceed $1 billion
annually.  The disease results in a quarter of a million
hospitalizations annually as well as more than 30,000 deaths
annually.  The report from the recent meeting "NCI Roundtable on
Prostate Cancer:  Future Research Directions" (Reported in Cancer
Research, 51: 2498, 1991) contains information and recommendations
defining areas of research that could advance the understanding and
management of prostate cancer.  Potential applicants requesting
support for this area of research are urged to acquaint themselves
with the report.

Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center for Research
Resources may wish to identify the GCRC as a resource for conducting
the proposed research.  If so, a letter of agreement from either the
GCRC program director or Principal Investigator may be included with
the application.

SPECIAL REQUIREMENTS

Successful applicants are expected to attend a yearly meeting of
Center Directors convened by the NIDDK.  Funds to support travel to
this meeting may be requested in the budget proposed for the Center.

STUDY POPULATIONS

It is NIH policy that women and minorities must be included in
clinical study populations unless there is a good reason to exclude
them.  The study design must seek to identify any pertinent gender or
minority population differences.

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy is that applicants for NIH clinical research grants and
cooperative agreements are required to include minorities and women
in study populations so that research findings can be of benefit to
all persons at risk of the disease, disorder or condition under
study; special emphasis must be placed on the need for inclusion of
minorities and women in studies of diseases, disorders and conditions
which disproportionately affect them.  This policy is intended to
apply to males and females of all ages.  If women or minorities are
excluded or inadequately represented in clinical research,
particularly in proposed population-based studies, a clear compelling
rationale must be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group.  In addition, gender and
racial/ethnic issues must be addressed in developing a research
design and sample size appropriate for the scientific objectives of
the study.  This information must be included in the form PHS 398
(rev. 9/91) in Item 4 (Research Design and Methods) of the Research
Plan AND summarized in Item 5, Human Subjects.  Applicants are urged
to assess carefully the feasibility of including the broadest
possible representation of minority groups.  However, NIH recognizes
that it may not be feasible or appropriate in all research projects
to include representation of the full array of United States
racial/ethnic minority populations; i.e., Native Americans [including
American Indians or Alaskan Natives], Asian/Pacific Islanders,
Blacks, Hispanics.

The rationale for studies on single minority population groups should
be provided.

For the purpose of this policy, clinical research is defined as human
biomedical and behavioral studies of etiology, epidemiology,
prevention [and preventive strategies], diagnosis, or treatment of
diseases, disorders or conditions, including but not limited to
clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include human tissues from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

If the required information is not contained within the application,
the application will be returned without review.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
women or minorities in a study design is inadequate to answer the
scientific question(s) addressed AND the justification for the
selected study population is inadequate, it will be considered a
scientific weakness or deficiency in the study design and reflected
in assigning the priority score to the application.

All applications for clinical research submitted to NIH are required
to address these policies.  NIH funding components will not award
grants or cooperative agreements that do not comply with these
policies.

LETTER OF INTENT

Prospective applicants are asked to submit, by March 8, 1993, a
letter of intent that includes a descriptive title of the proposed
research, the name, address, and telephone number of the Principal
Investigator, the identities of other key personnel and participating
institutions, and the number and title of the RFA in response to
which the application may be submitted.

Although a letter of intent is not required, is not binding, and does
not enter into the review of subsequent applications, the information
that it contains is helpful in planning for the review of
applications.  It allows NIDDK staff to estimate the potential review
workload and to avoid possible conflict of interest in the review.

The letter of intent is to be sent to:

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 605
Bethesda, MD  20892
Telephone:  (301) 496-7083
FAX:  (301) 402-1277

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for these grants.  The form is available from most
institutional offices of sponsored research and from the Office of
Grants Inquiries, Division of Research Grants, National Institutes of
Health, 5333 Westbard Avenue, Room 449, Bethesda, Maryland 20892,
telephone (301) 496-7441.

The RFA label available in the application form must be affixed to
the bottom of the face page.  Failure to use this label could result
in delayed processing of the application such that it may not reach
the review committee in time for review.  In addition, the RFA title
and number must be typed on line 2a of the face page of the
application form and check the YES box.

Application must include the following items:

o  A Table of Contents;

o  A Rationale for the proposed Center and a Statement of Objectives;

o  Institutional Environment and Resources;

o  Organization and Administrative Structure of the Center;

o  Specific Managerial Responsibilities for the Center;

o  Travel funds in the proposed budget for an annual meeting of
Center Directors;

o  A description of the method for the replacement of the Center
Director (should the need arise);

o  A description of the proposed research projects;

o  A description of the proposed cores;

o  A description of the procedure to be used for the
addition/deletion of cores and projects during the proposed period of
operation;

o  A description of the administrative relationship of the Center to
the applicant institution.

Submit a signed, typewritten original of the application, including
the Checklist, and three signed, exact photocopies, in one package
to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

At time of submission, two additional copies of the application must
also be sent under separate cover to:

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 605
Bethesda, MD  20892

Applications must be received by April 9, 1993.  If an application is
received after that date, it will be returned to the applicant.

REVIEW CONSIDERATIONS

Upon receipt, applications will be initially reviewed for
completeness and responsiveness.  Incomplete applications or
non-responsive applications will be returned to the applicant without
further consideration.  Evaluation for responsiveness to the program
requirements and criteria stated in the RFA is an NIDDK staff
function.

Those applications that are complete and responsive will be evaluated
in accordance with the criteria stated below for scientific/technical
merit by an appropriate peer review group convened by the NIDDK.  If
the number of applications is large compared to the number of awards
to be made, a preliminary scientific peer review may be conducted and
applications withdrawn from further competition when they are not
competitive for the award.  The NIDDK will notify the applicant and
institutional official of this action.

Those applications judged to be competitive will be reviewed for
scientific and technical merit in accordance with the usual NIH peer
review procedures by an initial review group specifically convened
for this RFA.  Following this review, the applications will be given
a secondary review by the NIDDK Advisory Council unless not
recommended for further consideration by the initial review group.

The review criteria for individual research projects include:

o  The scientific, technical or medical significance and originality
of the proposed research;

o  The feasibility and adequacy of the experimental design;

o  The degree to which projects link basic and clinical research;

o  The qualifications and research experience of the proposed
personnel;

o  The availability of resources necessary for the research;

o  The appropriateness of the budget and timetable in relation to the
scope of the proposed research;

The review criteria for scientific cores include:

o  The appropriateness and utility of the core to the proposed
Center;

o  Each core unit must provide facilities or services to at least two
research projects recommended for approval;

o  The quality of the proposed facilities or services including
administrative arrangements for utilizing the core;

o  The qualifications, experience, and commitment of the personnel
involved in the core;

o  The appropriateness of the budget.

The review criteria for the overall Center program include:

o  The scientific merit of the program as a whole;

o  The significance of the overall goals of the Center;

o  The cohesiveness and multidisciplinary scope of the Center and the
coordination and interrelationship of the projects and cores to the
common theme of the Center;

o  The leadership, scientific expertise, and commitment of the
proposed Center Director.

Administrative Considerations:

o  The institutional environment for and resources available to
Center investigators;

o  The institutional commitment to the proposed Center;

o  The administrative leadership necessary to provide for the quality
control of supported projects in the Center, the allocation of funds,
and the ability to foster communication and cooperation among Center
investigators;

o  The appropriateness of the budget in relation to the proposed
activities of the Center;

o  The adequacy of addressing the protection of human subjects,
animal welfare, and biohazard issues.

AWARD CRITERIA

The anticipated date of award is September 30, 1993. Factors that
will be taken into consideration in making awards include the
scientific merit of the proposed Center as determined by peer review
and the availability of funds.

Schedule

Letter of Intent:     March 8, 1993
Application Receipt:  April 9, 1993
Initial Review:       July 1993
Second Level Review:  September 13-14, 1993
Anticipated Award:    September 30, 1993

INQUIRIES

Written and telephone inquiries concerning this RFA are encouraged.

Inquiries regarding non-cancer programmatic issues may be directed
to:

Ralph L. Bain, Ph.D.
Director, Centers Program
Division of Kidney, Urologic, and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 3A-05
Bethesda, MD  20892
Telephone:  (301) 496-7574

Inquiries regarding cancer-related programmatic issues may be
directed to :

Andrew Chiarodo, Ph.D.
Chief, Organ Systems Coordinating Branch
Centers, Training, and Resources Program
Division of Cancer Biology, Diagnosis and Centers
National Cancer Institute
Executive Plaza North, Suite 316
Bethesda, MD  20892
Telephone:  (301) 496-8528

Inquiries regarding fiscal matters may be directed to:

Ms. Helen Ling
Grants Management Specialist
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 649
Bethesda, MD  20892
Telephone:  (301) 496-7467

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance No. 93.849.  Awards are made under authorization of the
Public Health Service Act, Title IV, Part A (Public Law 78-410, as
amended by Public Law 99-158, 42 USC 241 and 285) and administered
under PHS grants policies and Federal Regulations 42 CFR 52 and 45
CFR Part 74.  This program is not subject to the intergovernmental
review requirements of Executive Order 12372 or Health Systems Agency
review.


$$XID RFA AI9303 AI-93-03 P1O1 *****************************************

BASIC BIOLOGY AND PATHOGENESIS OF HUMAN TUBERCULOSIS

NIH GUIDE, Volume 21, Number 45, December 18, 1992

RFA:  AI-93-03

P.T. 34; K.W. 0745020, 0715125, 0710070, 0785035, 0710030, 0755010

National Institute of Allergy and Infectious Diseases

Letter of Intent Receipt Date:  January 22, 1993
Application Receipt Date:  March 23, 1993

PURPOSE

The Respiratory Diseases Branch of the Division of Microbiology and
Infectious Diseases and the Developmental Therapeutics Branch of the
Division of AIDS of the National Institute of Allergy and Infectious
Diseases (NIAID) invite applications for research on the basic
structural and functional biology and pathogenic mechanisms of
Mycobacterium tuberculosis.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000,"
a PHS-led national activity for setting priority areas.  This Request
for Applications (RFA), Basic Biology and Pathogenesis of Human
Tuberculosis, is related to the priority areas of immunity,
infectious diseases, and HIV infection.  Potential applicants may
obtain a copy of "Healthy People 2000" (Full Report:  Stock No.
017-001-00474-0) or "Healthy People 2000" (Summary Report:  Stock No.
017-001-00473-1) through the Superintendent of Documents, Government
Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238).

ELIGIBILITY REQUIREMENTS

Domestic and foreign non-profit and for-profit organizations and
institutions, governments and their agencies, are eligible to apply.
Minorities and women are encouraged to apply.  Foreign institutions
are not eligible for the First Independent Research Support and
Transition (FIRST) (R29) award.  Applications from or involving
minority institutions or women's institutions are encouraged.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) individual
research project grant (R01), and the FIRST (R29) award.
Responsibility for the planning, direction, and execution of the
proposed project will be solely that of the applicant.  The total
project period for applications submitted in response to this RFA may
not exceed five years.

This RFA is a one-time solicitation.  Future unsolicited competing
applications will compete with investigator-initiated applications
and be reviewed according to customary review procedures.

FUNDS AVAILABLE

The estimated total funds (direct and indirect costs) available for
the first year of this program will be $1,000,000.  In fiscal year
1993, the NIAID plans to fund at least four R01s and/or R29s.  This
level of support is dependent on the receipt of a sufficient number
of applications of high scientific merit.

RESEARCH OBJECTIVES

Background

A century ago, tuberculosis (TB) was a leading cause of death in the
United States.  Through the efforts of researchers, physicians, and
public health officials, as well as through improvements in living
conditions and the introduction of effective drug therapy, the number
of TB cases and deaths in the United States declined steadily for 40
years.  This trend stopped in 1985.  The number of cases is now
increasing.  The new cases of TB in the U.S. reported to the Centers
for Disease Control were 22,517 in 1987, 23,495 in 1989 and 26,283 in
1991.  This resurgence of TB is a matter of grave concern.  In the
United States TB is responsible for about 2,000 deaths annually.  An
estimated 10 million persons in the United States are presently
infected with the TB organism and have the potential to develop
clinical TB (active disease) at some time in their lives.  Globally,
TB is an even more serious threat.  An estimated 8 million new TB
cases and 2.9 million TB deaths occur each year. (Science, Vol. 21,
p1055-1064, Aug. 21, 1992).

The recent rise in tuberculosis cases reported in the United States
and elsewhere is attributed, at least in part, to the heightened
susceptibility to TB infections of HIV-positive persons.  Other
factors, including intravenous drug abuse, the increased influx of
immigrants from less developed nations, and poor socio-economic
status, also contribute to this rise.  The concern of health
officials about the number of cases is intensified by the recent
growth in the number of isolates of multi-drug-resistant M.
tuberculosis (MDRTB).  The background to these developments is
documented in publications of the Centers for Disease Control (e.g.,
Morbidity and Mortality Weekly Reports, March 1, 1991, Vol. 40, No. 8
and June 19, 1992,  Vol. 41, No. RR-11).

Despite advances in diagnosis and treatment made during the 100 years
since the identification of M. tuberculosis, serious problem areas
remain.  A clearer understanding of the structural and functional
biology of the organism could provide insight into both pathogenic
mechanisms and the immunologic responses evoked in the infected host.
 Sensitive and specific methods for rapid, reliable diagnosis of
tuberculosis are urgently needed.  Treatment of active tuberculosis
also remains an area of interest.  The means to shorten the treatment
course and hence improve both patient compliance and lower costs is
an important goal.  The emergence of resistant organisms is a matter
of particular concern to health officials.  The case fatality rate
for TB resistant to two or more drugs (MRDTB) is 40 to 60 percent and
the overall costs of treatment of these cases is five times higher.
Patients often fail to complete the long term drug treatments needed
to cure TB infections, an action that encourages both relapse and the
emergence of resistant organisms.  In conjunction with this,
methodologies for the rapid, reliable identification of MDRTB in
clinical specimens and in laboratory cultures are needed.

Progress in all areas of clinical tuberculosis research is contingent
upon an improved understanding of the basic structural and molecular
biology of M. tuberculosis.  Studies of the immunology, pathogenesis,
virulence factors, and molecular bacteriology of this organism are
thus of great importance if we are to achieve our clinical research
objectives.

Research Objectives and Scope

Applications are encouraged that involve a coordinated
multi-disciplinary approach to investigate M. tuberculosis and/or its
interactions with its host (including animal models).  Applications
that involve an integration of basic and clinical sciences will be
given favorable consideration.  The aim of these efforts should be a
greater understanding of mechanisms of pathogenesis, immune evasion,
virulence factors or host response and/or lead to improvements in the
diagnosis, treatment or prevention of tuberculosis.  These areas may
include, but are not limited to, the following:

o  Identify and characterize virulence factors important in the
pathogenesis of tuberculosis.

o  Characterize the role(s) of tumor necrosis factor and other
cytokines and soluble factors that affect the course of the disease.

o  Develop improved in vitro or animal models for basic and applied
studies.

o  Characterize cell surface antigens and describe their interactions
with components of the host immune system.

o  Characterize the response of the host to natural infection and
define the correlates of protective immunity.

o  Characterize immune mechanisms underlying successful inhibition of
growth and persistence of tubercle bacilli in the body.  Define the
mechanisms by which M. tuberculosis persists in a quiescent state,
and conditions under which reactivation of infection may occur.

o  Characterize mechanisms underlying drug resistance, particularly
in MDRTB.

o  Develop improved methods for rapid, reliable identification of
drug-sensitive and drug-resistant strains of M. tuberculosis,
including MDRTB, in clinical specimens and in laboratory cultures.

The areas outlined above are not intended to be all-inclusive, nor
are they all required.  All research strategies designed to improve
markedly the understanding of the pathogenic mechanisms operative in
tuberculosis, or with the potential for improving current diagnosis,
treatment, and prevention modalities, are encouraged.

SPECIAL REQUIREMENTS

NIAID program staff will organize annual meetings that Principal
Investigators and other key members (as designated by the Principal
Investigators) of the projects will be encouraged to attend to
discuss progress.  This will facilitate overall program planning and
development, evaluation of the feasibility of planned approaches, and
will promote productive interactions among the awardees.  Funds for
travel to these meetings should be included in the budget.  NIAID
program staff will also ensure and arrange for the participation in
these meetings of investigators from other relevant NIAID-supported
tuberculosis research projects, if appropriate, in order to further
promote productive interactions.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy is that applicants for NIH clinical research grants and
cooperative agreements will be required to include minorities and
women in study populations so that research findings can be of
benefit to all persons at risk of the disease, disorder or condition
under study; special emphasis should be placed on the need for
inclusion of minorities and women in studies of diseases, disorders
and conditions which disproportionately affect them.  This policy is
intended to apply to males and females of all ages.  If women or
minorities are excluded or inadequately represented in clinical
research, particularly in proposed population-based studies, a clear
compelling rationale should be provided.

The composition of the proposed study populations must be described
in terms of gender and racial/ethnic group, together with a rationale
for its choice.  In addition, gender and racial/ethnic issues should
be addressed in developing a research design and sample size
appropriate for the scientific objectives of the study.  This
information should be included in the form PHS 398 (rev. 9/91) in
Sections 1-4 of the Research Plan AND summarized in Section 5, Human
Subjects.

Applicants are urged to assess carefully the feasibility of including
the broadest possible representation of minority groups.  However,
NIH recognizes that it may not be feasible or appropriate in all
research projects to include representation of the full array of
United States racial/ethnic minority populations (i.e., Native
Americans including American Indians or Alaskan Natives,
Asian/Pacific Islanders, Blacks, Hispanics).  The rationale for
studies on single minority population groups should be provided.

For the purpose of this policy, clinical research includes human
biomedical and behavioral studies of etiology, epidemiology,
prevention (and preventive strategies), diagnosis, or treatment of
diseases, disorders or conditions, including but not limited to
clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include human tissues from women and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.  For
foreign awards, the policy on inclusion of women applies fully; since
the definition of minority differs in other countries, the applicant
must discuss the relevance of research involving foreign populations
groups to the United States' populations, including minorities.

If the required information is not contained within the application,
the application will be returned.  Peer reviewers will address
specifically whether the research plan in the application conforms to
these policies.  If the representation of women or minorities in a
study design is inadequate to answer the scientific question(s)
addressed AND the justification for the selected study population is
inadequate, it will be considered a scientific weakness or deficiency
in the study design and will be reflected in assigning the priority
score to the application.

All applications for clinical research submitted to NIH are required
to address these policies.  NIH funding components will not support
applications that do not comply.

LETTER OF INTENT

Prospective applicants are asked to submit, by January 22, 1993, a
letter of intent that includes a descriptive title of the proposed
research, the name, address and telephone number of the Principal
Investigator, the identities of other key personnel and the
participating institution, and the number and title of the RFA in
response to which the application may be submitted.  Although a
letter of intent is not required, is not binding, and does not enter
into the review of subsequent applications, the information allows
NIAID staff to estimate the potential review workload and avoid
conflict of interest in the review.

The letter of intent is to be sent to  Dr. Olivia Preble at the
address listed under INQUIRIES.

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for these grants.  These forms are available at most
institutional offices of sponsored research or business offices and
from the Office of Grants Inquiries, Division of Research Grants,
National Institutes of Health, Westwood Building, Room 449, Bethesda,
MD 20892, telephone 301/496-7441.  The deadline for receipt of
applications in response to this RFA is March 23, 1993.  Applicants
for FIRST (R29) awards must include at least three sealed letters of
reference attached to the face page of the original application.
FIRST award applications submitted without the required number of
reference letters will be considered incomplete and will be returned
without review.

Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center of Research Resources
may wish to identify the Center as a resource for conducting the
proposed research.  If so, a letter of agreement from the GCRC
Program Director should be included in the application material.

The RFA label available in the application form must be affixed to
the bottom of the face page.  Failure to use this label could result
in delayed processing of the application such that it may not reach
the review committee in time for review.  In addition, the "Yes" box
must be marked and the RFA title (Basic Biology and Pathogenesis of
Human Tuberculosis) and number (AI-93-03) must be typed on line 2a of
the face page of the application.

Submit a signed, typewritten original of the application, including
the Checklist and three signed single-sided photocopies, in one
package, to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

At the time of submission to DRG, two additional exact copies must be
sent to Dr. Olivia Preble at the address listed under INQUIRIES.

Applications received after the deadline will be returned without
review.

The Division of Research Grants (DRG) will not accept any application
in response to this announcement that is essentially the same as one
currently pending initial review, unless the applicant withdraws the
pending application.  The DRG will not accept any application that is
essentially the same as one already reviewed.  This does not exclude
the submission of substantial revisions of application already
reviewed.  These applications must, however, include an introduction
addressing the previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications and supporting material will be reviewed
by the DRG for completeness and by NIAID staff for responsiveness to
the RFA.  Incomplete applications will be returned without further
consideration.  If the application is not responsive to the RFA,
NIAID staff will contact the applicant to determine whether to return
the application or submit it for review in competition with
unsolicited applications at the next review cycle.

Applications may be triaged by an NIAID peer review group on the
basis of relative competitiveness.  The NIH will withdraw from
further competition those applications judged to be non-competitive
for award and notify the applicant Principal Investigator and
institutional official.  Those applications that are complete and
responsive will be evaluated in accordance with the criteria stated
below for scientific/technical merit by an appropriate peer review
group convened by the NIAID.  The second level of review will be
provided by the National Advisory Allergy and Infectious Diseases
Council.

Review criteria for applications received in response to an RFA are
generally
the same as those for unsolicited applications, namely:

o  Scientific, technical, or medical significance and originality of
the proposed research.

o  Appropriateness and adequacy of the experimental approach and
methodology proposed to accomplish the research.

o  Qualification and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research.

o  Availability of resources to carry out the proposed research.

o  Appropriateness of the proposed budget and duration of the project
in relation to the proposed research.

AWARD CRITERIA

The anticipated date of award is September 30, 1993.

The primary criterion for award is technical and scientific merit as
judged by peer review and reflected in the priority score.
Additional criteria are availability of funds and the number of
meritorious applications received in response to this RFA.

INQUIRIES

Written and telephone inquiries concerning this RFA are encouraged.
The opportunity to clarify issues or questions from potential
applicants is welcome.

Direct inquiries regarding programmatic issues to:

Dr. John Foulds
Tuberculosis Program Officer
Respiratory Diseases Branch
Division of Microbiology and Infectious Diseases
National Institute of Allergy and Infectious Diseases
Solar Building, Room 3A31
Bethesda, MD  20892
Telephone:  (301) 496-5305
FAX:  (301) 496-8030

Direct inquiries regarding the review of applications to:

Dr. Olivia Preble
Chief, Microbiology and Immunology Review Section
Scientific Review Branch
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4C20
Bethesda, MD  20892
Telephone:  (301) 496-8208
FAX:  (301) 402-2638

Direct inquiries regarding fiscal matters to:

Mr. Todd Ball
Chief, MID Grants Management Section
Grants Management Branch
Division of Extramural Activities
National Institute of Allergy and Infectious Diseases
Solar Building, Room 4B35
Bethesda, MD  20892
Telephone:  (301) 496-7075

The mailing address for sending applications, letters of intent, or
other correspondence to NIAID staff in the Solar Building is the
central mailing address for the NIH.  Applicants who use express mail
or a courier service are advised to follow the carrier's requirements
for showing a street address.  The address for the Solar Building is:

6003 Executive Boulevard
Rockville, Maryland  20852

SCHEDULE

Letter of intent date:     January 22, 1993
Application receipt date:  March 23, 1993
Scientific review date:    July 1993
Advisory Council date:     September 1993
Earliest award date:       September 30, 1993

AUTHORITY AND REGULATIONS

This program is supported under authorization of the Public Health
Service Act, Sec. 301 (c), Public Law 78-410, as amended.  The
Catalogue of Federal Domestic Assistance Citation is Sec. 93.856,
Microbiology and Infectious Diseases Research.  Awards will be
administered under PHS grants policies and Federal Regulations 42 CFR
Part 52 and 45 CFR Part 74.  This program is not subject to the
intergovernmental review requirements of Executive Order 12372 or
Health Systems review.