+---------------------------------+---+-------+--------+-----------------+
| # BIOGRAPHICAL SKETCH           |   |       |        |                 |
|                                 |   |       |        |                 |
| Provide the following           |   |       |        |                 |
| information for the key         |   |       |        |                 |
| personnel and other significant |   |       |        |                 |
| contributors in the order       |   |       |        |                 |
| listed on Form Page 2.\         |   |       |        |                 |
| Follow this format for each     |   |       |        |                 |
| person. **DO NOT EXCEED FOUR    |   |       |        |                 |
| PAGES.**                        |   |       |        |                 |
+---------------------------------+---+-------+--------+-----------------+
|                                 |   |       |        |                 |
+---------------------------------+---+-------+--------+-----------------+
| NAME                            |   | POS   |        |                 |
|                                 |   | ITION |        |                 |
| **Michael R. Zile, M.D.**       |   | TITLE |        |                 |
|                                 |   |       |        |                 |
|                                 |   | Staff |        |                 |
|                                 |   | Phys  |        |                 |
|                                 |   | ician |        |                 |
|                                 |   | /Dire |        |                 |
|                                 |   | ctor, |        |                 |
|                                 |   | MICU  |        |                 |
|                                 |   | (     |        |                 |
|                                 |   | VAMC) |        |                 |
|                                 |   |       |        |                 |
|                                 |   | Ch    |        |                 |
|                                 |   | arles |        |                 |
|                                 |   | Ezra  |        |                 |
|                                 |   | D     |        |                 |
|                                 |   | aniel |        |                 |
|                                 |   | Prof  |        |                 |
|                                 |   | essor |        |                 |
|                                 |   | of    |        |                 |
|                                 |   | Med   |        |                 |
|                                 |   | icine |        |                 |
|                                 |   | (     |        |                 |
|                                 |   | MUSC) |        |                 |
+---------------------------------+---+-------+--------+-----------------+
| eRA COMMONS USER NAME           |   |       |        |                 |
|                                 |   |       |        |                 |
| zilemr                          |   |       |        |                 |
+---------------------------------+---+-------+--------+-----------------+
| EDUCATION/TRAINING *(Begin with |   |       |        |                 |
| baccalaureate or other initial  |   |       |        |                 |
| professional education, such as |   |       |        |                 |
| nursing, and include            |   |       |        |                 |
| postdoctoral training.)*        |   |       |        |                 |
+---------------------------------+---+-------+--------+-----------------+
| INSTITUTION AND LOCATION        | D |       | Y      | FIELD OF STUDY  |
|                                 | E |       | EAR(s) |                 |
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|                                 | ) |       |        |                 |
|                                 | * |       |        |                 |
+---------------------------------+---+-------+--------+-----------------+
| Knox College, Galesburg,        | B |       | 1974   | Biology         |
| Illinois                        | . |       |        |                 |
|                                 | A |       |        |                 |
|                                 | . |       |        |                 |
+---------------------------------+---+-------+--------+-----------------+
| Rush University Medical School, | M |       | 1977   | Medicine        |
| Chicago, Illinois               | . |       |        |                 |
|                                 | D |       | 197    | Internal        |
| Rush-Presbyterian-St.Luke's     | . |       | 7-1980 | Medicine        |
| Hospital Chicago,IL             |   |       |        |                 |
|                                 | R |       |        |                 |
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|                                 | y |       |        |                 |
+---------------------------------+---+-------+--------+-----------------+
| Tufts-New England Medical       | F |       | 198    | Clinical        |
| Center, Boston, MA              | e |       | 0-1982 | Cardiology      |
|                                 | l |       |        |                 |
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|                                 | i |       |        |                 |
|                                 | p |       |        |                 |
+---------------------------------+---+-------+--------+-----------------+
| Boston VA Medical Center,       | F |       | 198    | Cardiology      |
| Boston, MA                      | e |       | 2-1984 | Research        |
|                                 | l |       |        |                 |
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+---------------------------------+---+-------+--------+-----------------+

**A. Positions and Honors**

**[Positions and Employment]{.underline}**

1982-1988 Director, Cardiac Catheterization Laboratory, Dept VA Medical
Center, Boston, MA

1984-1988 Director, Research Laboratory, Depart VA Medical Center,
Boston, MA

1982-1988 Assistant Professor of Medicine, Tufts University School of
Medicine, Boston, MA

1988-1989 Associate Professor of Medicine, Tufts University School of
Medicine, Boston, MA

1988-1993 Associate Professor of Medicine, Medical University of South
Carolina, Charleston, SC

1989- Director, Medical Intensive Care Unit, Dept VA Medical Center,
Charleston, SC

1993- Professor of Medicine, Medical University of South Carolina,
Charleston, SC

1994- Adjunct Professor, Department of Bioengineering, Clemson
University, Clemson, SC

1999- Charles Ezra Daniel Professor of Medicine, Medical University of
South Carolina,

Charleston, SC

**[Other Experience and Professional Memberships]{.underline}**

1980 American Heart Association,(Fellow, Program Committee, Grant
Review)

1987 American College of Cardiology (Fellow, Program Committee, South
Carolina President's Council)

1996 Heart Failure Society of America (Program Committee, Education
Committee, Executive Council 2007-)

1999 American Physiological Society (Fellow, Program Committee)

1996 Editorial Boards: Journal of the American College of Cardiology
(1996-2000, 2003- ),

Circulation (2000- ), Congestive Heart Failure (2003- )

2003 NHLBI-NIH Working Group on Strategic Directions in Congestive Heart
Failure

**[Honors]{.underline}**

1997 Horace Smithy Award for Heart Research in SC, American Heart
Association

1999 Charles Ezra Daniel Endowed Chair in Cardiology, Medical University
of South Carolina

2003 Member, Association of University Cardiologists

2002-2007 Member, ABIM Subspecialty Board on Cardiovascular Disease

2007-2011 Chair, ABIM Subspecialty Board on Cardiovascular Disease

2007-2011 Member, ABIM Board of Directors, Internal Medicine

**B. Selected peer-reviewed publications (Selected from over 145
peer-reviewed publications)**

1\. Roten L, Nemoto S, Simsic J, Coker ML, Rao J, Baicu S, Defreyte G,
Solloway PJ, **Zile MR**, Spinale FG: Effects of gene deletion of the
tissue inhibitor of the matrix metalloproteinase-type 1 (TIMP-1) on left
ventricular geometry and function in mice. J Mol Cell Cardiol,
32:109-120, 2000.

2\. Koide M, Hamawaki M, Narishige T, Sato H, Defreyte G, **Zile MR**,
Cooper G IV, Carabello BA: Microtubule depolymerization normalizes in
vivo and in vitro myocardial contractile function in dogs with pressure
overload left ventricular hypertrophy. Circulation, 102:1045-1052, 2000.

3\. Laser M, Willey C, Jiang W, Cooper IV, Menick D, **Zile MR**,
Kuppuswamy D: Integrin activation and focal complex formation in cardiac
hypertrophy. J Biol Chem, 275(45): 35624-30, 2000.

4\. Gramling-Babb P, **Zile MR**, Reeves ST: Preliminary report on high
thoracic epidural analgesia (HTEA): Relationship between its therapeutic
effect and myocardial blood flow as assessed by stress thallium
distribution. J Cardiothorac Vasc Anesth, 14:657-661, 2000.

5\. **Zile MR**, Green R, Schuyler GT, Aurigemma G, Miller C, Cooper G,
IV: Mechanisms causing myocardial failure in man: Cytoskeletal changes
in patients with pressure overload hypertrophy (POH). J Am Coll Card,
37: 1080-4, 2001.

6\. Ishibashi Y, Rembert J, Carabello B, Nemoto S, Hamawaki M, **Zile
MR**, Greenfield JC, Cooper G, IV: Normal myocardial function in severe
right ventricular volume overload hypertrophy. Am J Physiol, 280:H11-16,
2001.

7\. Walker CA, Ergul A, Grubbs A, **Zile MR**, Zellner JL, Crumbley AJ,
Spinale F: -Adrenergic and endothelin receptor interaction in dilated
human cardiomyopathic myocardium. J Card Fail, 7: 129-137, 2001.

8\. **Zile MR**, Gaasch WH, Carroll JD, Feldman MD, Aurigemma GP, Schaer
GL, Ghali JK, Liebson PR. Heart failure with a normal ejection fraction.
Is measurement of diastolic function necessary to make the diagnosis of
diastolic heart failure? Circulation 104:779-782, 2001.

9\. **Zile MR**, Brutsaert DL. New concepts in diastolic dysfunction and
diastolic heart failure. Part One: Diagnosis, prognosis, measurements of
diastolic function. Circulation 105:1487-1393, 2002.

10\. Harris TS, Baicu CF, Conrad CH, **Zile MR**. Constitutive
properties of hypertrophied myocardium: cellular contributions to
changes in myocardial stiffness. Am J Physiol 282:H2173-H2182, 2002.

11\. Stroud JD, Baicu CF, Barnes MA, Spinale FG, **Zile MR**.
Viscoelastic properties of pressure overload hypertrophied myocardium:
effect serine protease treatment. Am J Physiol 282:H2324-2335,2002.

12\. Baicu CF, Stroud JD, Livesay VA, Hapke E, Holder J, Spinale FG,
**Zile MR**. Changes in the extracellular collagen matrix alter systolic
performance both in normal and pressure overload hypertrophied
myocardium. Am J Physiol 284:H122-32, 2003.

13\. Mukherjee R, Widener CE, Brinsa TA, Dowdy KB, Scott AA, Escobar GP,
Joffs C, Lucas DG, **Zile MR,** Spinale FG. Myocardial infarct expansion
and matrix metalloproteinase inhibition, Circulation, 107:618-625, 2003.

14\. King MK, Coker ML, Goldberg A, McElmurray JH, Gunasinghe HR,
Mukherjee R, **Zile MR**, O'Neill TP, Spinale FG. Selective matrix
metalloproteinase inhibition with developing heart failure: effects on
left ventricular function and structure. Circ Res 92:177-185, 2003.

15\. Ishibashi Y, Takahashi M, Isomatsu Y, Qiao F, Iijima Y, Shiraishi
H, Simsic JM, Baicu CF, Robbins J**, Zile MR**, Cooper G. Role of
microtubules versus myosin heavy chain isoforms in the contractile
dysfunction of hypertrophied murine cardiocytes:. Am J Physiol,
285:H1270-85, 2003.

16\. **Zile MR**. Heart failure with preserved ejection fraction: Is
this diastolic heart failure? J Am Coll Cardiol 41:1519-1522, 2003.

17\. **Zile MR**, Gaasch WH, Little W, Francis G, Tavazzi L, Cleland J,
Davies M, for the MCC-135 GO1 investigators. A phase II, double-blind,
randomozed, placebo-controlled, dose comparative study of the efficacy,
tolerability, and safety of MCC-135 in subjects with chronic heart
failure, NYHA class II/III (MCC-135-GO1 Study): Rationale and Design*.*
J Cardiac Failure, 10:193-199, 2004.

18\. **Zile MR**, Baicu CF, Gaasch WH. Diastolic heart
failure-abnormalities in active relaxation and passive stiffness of the
left ventricle**.** N Engl J Med, 350:1953-9, 2004.

19\. Stroud RE, Deschamps AM, Lowry AS, Hardin AE, Mukherjee R, Lindsey
ML, Ramamoorthy S, **Zile MR**, Spencer WH, Spinale FG. Plasma
monitoring of the myocardial specific tissue inhibitor of
metalloproteinase-4 following alcohol septal ablation in hypertrophic
obstructive cardiomyopathy. J Card Failure, 11(2):124-30, 2005.

20\. Little WC, **Zile MR**, Kitzman DW, Hundley WG, O\'Brien TX,
deGroof RC. The Effect of Alagebrium Chloride (ALT-711), a Novel Glucose
Cross-Link Breaker, in the Treatment of Elderly Patients with Diastolic
Heart Failure. J Card Failure, 11(3):191-195, 2005.

21\. Ikonomidis JS, Hendrick JW, Parkhurst AM, Herron AR, Escobar PG,
Dowdy KB, Stroud RE, Hapke E, **Zile MR**, Spinale FG. Accelerated LV
remodeling after myocardial infarction in TIMP-1 deficient mice: effects
of exogenous MMP inhibition. Am J Physiol 288:H149-158, 2005.

22\. Baicu CF, **Zile MR**, Aurigemma GP, Gaasch WH. Left ventricular
performance, function, and contractility in patients with diastolic
heart failure. Circulation, 111(18):2306-2312, 2005.

23\. Aurigemma GP, **Zile MR,** Gaasch WH. Contractile behavior in the
left ventricle in diastolic heart failure: With special emphasis on
regional systolic function. Circulation 113: 296-304, 2006.

24\. Ahmed A, Rich MW, Fleg JL, **Zile MR**, Young JB, Kitzman DW, Love
TE, Aronow WS, Adams KF Jr, Gheorghiade M. Effects of digoxin on
morbidity and mortality in diastolic heart failure: The Ancillary
Digitalis Investigation Group Trial. Circulation, 114:397-403, 2006.

25\. Little WC, **Zile MR**, Klein A, Appleton CP, Kitzman DW,
Wesley-Farrington DJ. Effect of losartan and hydrochlorothiazide on
exercise tolerance in exertional hypertension and left ventricular
diastolic dysfunction. Am J Cardiol 93:383-385, 2006.

26\. Ahmed SH, Clark LL, Pennington WR, Webb CS, Bonnema DD, Leonardi
AH, McClure CD, Spinale FG, **Zile MR**. Matrix
metalloproteinases/tissue inhibitors of metalloproteinases: Relationship
between changes in proteolytic determinants of matrix composition and
structural, functional & clinical manifestations of hypertensive heart
disease. Circulation 113:2089-2096, 2006.

27\. Webb CS, Bonnema DD, Ahmed SH, Leonardi AH, McClure CD, Clark LL,
Stroud RE, Corn WC, Finklea L, **Zile MR,** Spinale FG. Specific
temporal profile of matrix metalloproteinase release occurs in patients
after myocardial infarction. Relation to left ventricular remodeling.
Circulation 114:1020-1027, 2006.

28\. Xu L, Renaud L, Müller JG, Baicu CF, Bonnema DD, Zhou H, Kappler
CS, Kubalak SW, Zile MR, Conway SJ, **Menick DR**. Regulation of NCX1
expression: Identification of regulatory elements mediating cardiac
specific expression and upregulation. J Biol Chem 281:34430-34440, 2006.

29\. Ahmed A, Rich MW, Sanders PW, Perry GJ, Bakris GL, **Zile MR,**
Love TE, Aban IB, Shlipak MG: Chronic kidney disease associated
mortality in diastolic versus systolic heart failure: A propensity
matched study. Am J Cardiol, 99:393-398, 2007.

30\. Ahmed A, **Zile MR**, Rich MW, Fleg JL, Adams KF Jr, Love TE, Young
JB, Aronow WS, Kitzman DW, Gheorghiade M, Dell'Italia LJ:
Hospitalizations due to unstable angina pectoris in diastolic and
systolic heart failure. Am J Cardiol, 99:460-464, 2007.

31\. **Zile MR**, LeWinter MM. Left ventricular end-diastolic volume is
normal in patients with heart failure and a normal ejection fraction. A
Renewed Consensus in Diastolic Heart Failure (editorial). J Am Coll
Cardiol, 49:982-985, 2007.

32\. Bonnema DD, Webb CS, Pennington WR, Stroud RE, Leonardi AE, Clark
LL, McClure CD, Finklea L, Spinale FG, **Zile MR**. Effects of Age on
Plasma Matrix Metalloproteinases (MMPs) and Tissue Inhibitor of
Metalloproteinases (TIMPs). J Card Fail, 13:530-540, 2007.

33\. Solomon SD, Janardhanan R, Verma A, Bourgoun M, Daley WL,
Purkayastha D, Lacourcière Y, Hippler SE, Fields H, Naqvi TZ, Mulvagh
SL, Arnold JMO, Thomas JD, **Zile MR**, Aurigemma GP for the Valsartan
In Diastolic Dysfunction (VALIDD) Investigators. Effect of angiotensin
receptor blockade and antihypertensive drugs on diastolic function in
patients with hypertension and diastolic dysfunction: a randomized
trial. Lancet, 369:2079-2087, 2007.

34\. McMurray JJ, Carson PE, Komajda M, McKelvie R, **Zile M**,
Ptaszynska A, Staiger C, Donovan JM, Massie BM. Heart failure with
preserved ejection fraction: Clinical characteristics of 4,133 patients
enrolled in the I-PRESERVE trial. Eur J Heart Fail, 10:149-156, 2008.

35\. Bourge RC, Abraham WT, Adamson PB, Aaron MF, Aranda JM Jr, Magalski
A, **Zile MR**, Smith AL, Smart FW, O'Shaughnessy MA, Jessup ML, Sparks
B, Naftel DL, Warner-Stevenson L on behalf of the COMPASS-HF Study
Group. Randomized Controlled Trial of an Implantable Continuous
Hemodynamic Monitor in Patients With Advanced Heart Failure. J Am Coll
Cardiol, 51:1073-1079, 2008.

36\. Spruill LS, Baicu CF, **Zile MR**, McDermott PJ. Selective
translation of mRNAs in the left ventricular myocardium of the mouse in
response to acute pressure overload. J Mol Cell Cardiol, 44:69-75, 2008.

37\. Willey CD, Palanisamy AP, Johnston RK, Mani SK, Shiraishi H,
Tuxworth WJ, **Zile MR**, Balasubramanian S, Kuppuswamy D. STAT3
Activation in Pressure-Overloaded Myocardium: Role for Integrins and the
Tyrosine Kinase BMX. Int J Biol Sci, 4(3):184-199, 2008.

38\. Farr MJ, Lang CC, LaManca JJ, **Zile MR**, Francis G, Tavazzi L,
Gaasch WH, St. John Sutton M, Itoh H, Mancini D; MCC-135 G01
Investigators. Cardiopulmonary exercise variables in diastolic versus
systolic heart failure. Am J Cardiol, 102 (2):203-206, 2008.

39\. Mani SK, Shiraishi H, Balasubramanian S, Yamane K, Chellaiah M,
Cooper G, Banik N, **Zile MR**, Kuppuswamy D. *In Vitro* Administration
of Calpeptin Attenuates Calpain Activation and Cardiomyocyte Loss in
Pressure Overload Feline Myocardium. Am J Physiol Heart Circ Physiol,
295(1):H314-326, 2008.

40\. Jang I-K, Weissman NJ, Picard MH, **Zile MR**, Pettigrew V, Shen S,
Tatsuno J, Hibberd MG, Tzivoni D, Wackers FJT, and the EVOLVE
Investigators: A randomized, double-blind, placebo-controlled study of
the safety and efficacy of intravenous MCC-135 as an adjunct to primary
percutaneous coronary intervention in patients with acute myocardial
infarction: Evaluation of MCC-135 for left ventricular salvage in acute
myocardial infarction (EVOLVE). Am Heart J, 155:113.31-113.38, 2008.

41\. Cheng G, **Zile MR**, Takahashi M, Baicu CF, Bonnema DD, Cabral F,
Menick DR, Cooper G IV: A Direct Test of the Hypothesis that Increased
Microtubule Network Density Contributes to Contractile Dysfunction of
the Hypertrophied Heart. Am J Physiol Heart Circ Physiol,
294:H2231-H2241, 2008.

42\. Gaasch WH, Delorey DE, St. John Sutton MG, **Zile MR**. Patterns of
Structural and Functional Remodeling of the Left Ventricle in Chronic
Heart Failure. Am J Cardiol, in press, 2008.

43\. Greenberg B, Czerska B, Delgado RM, Bourge R, **Zile MR**, Silver
M, Klapholz M, Haeusslein E, Mather P, Abraham WT, Neaton JD, Brown BS,
Parker IC, Konstam MA, on behalf of the MOMENTUM Investigators and
Coordinators. Effects of Continuous Aortic Flow Augmentation in Patients
with Exacerbation of Heart Failure, Inadequately Responsive to Medical
Therapy: Results of the Multi-center Trial of the Orqis® Medical
Cancion® system for the Enhanced Treatment of Heart Failure Unresponsive
to Medical Therapy (MOMENTUM). Circulation, in press, 2008.

**C. Research Support**

### **[Ongoing Research Support]{.underline}**

VA BLRD Merit (P.I.: Zile) 10/01/2006-09/30/2010

Department of Veterans Affairs

Diastolic Heart Failure: Role of the Extracellular Matrix

This VA Merit Review grant seeks to define the underlying mechanisms
which cause abnormal diastolic function and lead to the development of
diastolic heart failure. This study will focus on the molecular and
cellular mechanisms which control extra-cellular matrix (ECM) collagen
synthesis, post-translational modification and degradation. The Specific
Aims are: 1) Define the effects of pressure overload hypertrophy (POH)
on cardiac fibroblast function and determine whether changes in function
are dependent on increased advanced glycation end product (AGE) and the
fibroblast receptor for AGE (RAGE) interaction; 2) Determine whether
transgenic or pharmacological alterations in AGE/RAGE interactions alter
the left ventricle and ECM response to POH produced by transverse aortic
constriction in mice; 3) Examine changes produced by POH in signal
transduction cascades connecting AGE/RAGE binding to nuclear
translocation of transcription factors leading to increased expression
of profibrotic proteins.

**[Completed Research Support]{.underline}**

PO2-HL48788-15 (Program Director: Cooper) 08/01/1993-07/30/2008

NIH/NHLBI **Competing Renewal Submission Targeted for September 2008**

This NIH Program Project Grant seeks to establish the causes and
consequences of cardiac hypertrophic growth. Dr. Zile is Principal
Investigator for Program Grant Project #6, Co-Investigator Project #2,
Core Co-director for the Animal Model Core: The goal of Project #6
(Diastolic Heart failure: Defining Cardiocyte Mechanisms) will focus
upon the cellular mechanisms that cause increased cardiocyte stiffness.
This project will examine changes in calcium regulatory and cytoskeletal
proteins in models of diastolic congestive heart failure.

Role on Project: Principal Investigator of Project 6; Co-PI of Project
2; Director of Animal Model Core

D.  **Time/Effort Statement:** Research=65%; Clinical=25%;
    Teaching/Mentoring=9%; Administration=1%

This is a statement of overall effort including both VA and MUSC
appointments. Dr. Zile currently has an 8/8ths (40 hrs/wk) VA paid
appointment with the VAMC Charleston, SC and a paid faculty appointment
(20 hrs/wk) with the Medical University of South Carolina.

+-------------------------------+---+-------------------+---+-----------------+
| **OTHER SUPPORT**             |   |                   |   |                 |
+-------------------------------+---+-------------------+---+-----------------+
| **ZILE, Michael R. (M.D.)**   |   |                   |   |                 |
+-------------------------------+---+-------------------+---+-----------------+
| **[ACTIVE]{.underline}**      |   |                   |   |                 |
+-------------------------------+---+-------------------+---+-----------------+
| > VA BLRD Merit (Zile)        | 1 |                   | 3 |                 |
|                               | 0 |                   | . |                 |
|                               | / |                   | 6 |                 |
|                               | 1 |                   | c |                 |
|                               | / |                   | a |                 |
|                               | 0 |                   | l |                 |
|                               | 6 |                   | e |                 |
|                               | - |                   | n |                 |
|                               | 9 |                   | d |                 |
|                               | / |                   | a |                 |
|                               | 3 |                   | r |                 |
|                               | 0 |                   | ( |                 |
|                               | / |                   | V |                 |
|                               | 1 |                   | A |                 |
|                               | 0 |                   | ) |                 |
+-------------------------------+---+-------------------+---+-----------------+
| > Department of Veterans      |   |                   |   |                 |
| > Affairs \$125,000           |   |                   |   |                 |
+-------------------------------+---+-------------------+---+-----------------+
| > **Diastolic Heart Failure:  |   |                   |   |                 |
| > Role of the Extracellular   |   |                   |   |                 |
| > Matrix**                    |   |                   |   |                 |
+-------------------------------+---+-------------------+---+-----------------+
| > This VA Merit Review grant  |   |                   |   |                 |
| > seeks to define the         |   |                   |   |                 |
| > underlying mechanisms which |   |                   |   |                 |
| > cause abnormal              |   |                   |   |                 |
| > diastolicfunction and lead  |   |                   |   |                 |
| > to the development of       |   |                   |   |                 |
| > diastolic heart failure.    |   |                   |   |                 |
| > This study will focus on    |   |                   |   |                 |
| > the molecular and cellular  |   |                   |   |                 |
| > mechanisms which control    |   |                   |   |                 |
| > extra-cellular matrix (ECM) |   |                   |   |                 |
| > collagen synthesis,         |   |                   |   |                 |
| > post-translational          |   |                   |   |                 |
| > modification and            |   |                   |   |                 |
| > degradation. The Specific   |   |                   |   |                 |
| > Aims are: 1) Define the     |   |                   |   |                 |
| > effects of pressure         |   |                   |   |                 |
| > overload hypertrophy (POH)  |   |                   |   |                 |
| > on cardiac fibroblast       |   |                   |   |                 |
| > function and determine      |   |                   |   |                 |
| > whether changes in function |   |                   |   |                 |
| > are dependent on increased  |   |                   |   |                 |
| > advanced glycation end      |   |                   |   |                 |
| > product (AGE) and the       |   |                   |   |                 |
| > fibroblast receptor for AGE |   |                   |   |                 |
| > (RAGE) interaction; 2)      |   |                   |   |                 |
| > Determine whether           |   |                   |   |                 |
| > transgenic or               |   |                   |   |                 |
| > pharmacological alterations |   |                   |   |                 |
| > in AGE/RAGE interactions    |   |                   |   |                 |
| > alter the left ventricle    |   |                   |   |                 |
| > and ECM response to POH     |   |                   |   |                 |
| > produced by transverse      |   |                   |   |                 |
| > aortic constriction in      |   |                   |   |                 |
| > mice; 3) Examine changes    |   |                   |   |                 |
| > produced by POH in signal   |   |                   |   |                 |
| > transduction cascades       |   |                   |   |                 |
| > connecting AGE/RAGE binding |   |                   |   |                 |
| > to nuclear translocation of |   |                   |   |                 |
| > transcription factors       |   |                   |   |                 |
| > leading to increased        |   |                   |   |                 |
| > expression of profibrotic   |   |                   |   |                 |
| > proteins.                   |   |                   |   |                 |
+-------------------------------+---+-------------------+---+-----------------+
|                               |   |                   |   |                 |
+-------------------------------+---+-------------------+---+-----------------+
| > N01-HV-281-81-000 (Knapp)   | 0 |                   | 1 |                 |
|                               | 9 |                   | . |                 |
|                               | / |                   | 8 |                 |
|                               | 3 |                   | c |                 |
|                               | 0 |                   | a |                 |
|                               | / |                   | l |                 |
|                               | 0 |                   | e |                 |
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|                               | - |                   | d |                 |
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|                               | / |                   | r |                 |
|                               | 3 |                   | ( |                 |
|                               | 0 |                   | M |                 |
|                               | / |                   | U |                 |
|                               | 0 |                   | S |                 |
|                               | 9 |                   | C |                 |
|                               |   |                   | ) |                 |
+-------------------------------+---+-------------------+---+-----------------+
| > NIH/NHLBI \$127,000         |   |                   |   |                 |
+-------------------------------+---+-------------------+---+-----------------+
| > **The Cardiovascular        |   |                   |   |                 |
| > Proteomics Center**         |   |                   |   |                 |
+-------------------------------+---+-------------------+---+-----------------+
| > This study is devoted to    |   |                   |   |                 |
| > the development of new      |   |                   |   |                 |
| > proteomics technology while |   |                   |   |                 |
| > furthering cardiovascular   |   |                   |   |                 |
| > research. Dr. Zile's        |   |                   |   |                 |
| > project entitled            |   |                   |   |                 |
| > "Application of Proteomic   |   |                   |   |                 |
| > Analysis to Cardiovascular  |   |                   |   |                 |
| > Research in Diastolic Heart |   |                   |   |                 |
| > Failure" will use rat       |   |                   |   |                 |
| > models to investigate       |   |                   |   |                 |
| > divergent growth mechanisms |   |                   |   |                 |
| > and pathologies associated  |   |                   |   |                 |
| > with pressure overload      |   |                   |   |                 |
| > versus volume overload      |   |                   |   |                 |
| > cardiac hypertrophy. It     |   |                   |   |                 |
| > will also examine age and   |   |                   |   |                 |
| > sex related differences.    |   |                   |   |                 |
| > Two dimensional             |   |                   |   |                 |
| > electrophoresis and newly   |   |                   |   |                 |
| > developed methods of mass   |   |                   |   |                 |
| > spectroscopy will be        |   |                   |   |                 |
| > employed to identify        |   |                   |   |                 |
| > proteins and their post     |   |                   |   |                 |
| > translational modifications |   |                   |   |                 |
| > identified in these         |   |                   |   |                 |
| > studies.                    |   |                   |   |                 |
| >                             |   |                   |   |                 |
| > Role on Project: Principal  |   |                   |   |                 |
| > Investigator of Project 1   |   |                   |   |                 |
+-------------------------------+---+-------------------+---+-----------------+
| **[PENDING]{.underline}**     |   |                   |   |                 |
+-------------------------------+---+-------------------+---+-----------------+
|                               |   |                   |   |                 |
+-------------------------------+---+-------------------+---+-----------------+
| > PO1-HL04877 (Cooper)        |   | 8/01/09-06/30/14  |   |                 |
+-------------------------------+---+-------------------+---+-----------------+
| > NIH/NHLBI Competing Renewal |   |                   |   |                 |
| > to be submitted September   |   |                   |   |                 |
| > 2008                        |   |                   |   |                 |
+-------------------------------+---+-------------------+---+-----------------+
| > **Load-induced Cardiac      |   |                   |   |                 |
| > Hypertrophy in the Adult    |   |                   |   |                 |
| > Mammal**                    |   |                   |   |                 |
+-------------------------------+---+-------------------+---+-----------------+
| > This NIH Program Project    |   |                   |   |                 |
| > Grant seeks to establish    |   |                   |   |                 |
| > the causes and consequences |   |                   |   |                 |
| > of cardiac hypertrophic     |   |                   |   |                 |
| > growth. Dr. Zile is         |   |                   |   |                 |
| > Principal Investigator for  |   |                   |   |                 |
| > Program Grant Project #6,   |   |                   |   |                 |
| > Co-Investigator Project #2, |   |                   |   |                 |
| > Core Co-director for the    |   |                   |   |                 |
| > Animal Model Core: The goal |   |                   |   |                 |
| > of Project #6 (Diastolic    |   |                   |   |                 |
| > Heart failure: Defining     |   |                   |   |                 |
| > Cardiocyte Mechanisms) will |   |                   |   |                 |
| > focus upon the cellular     |   |                   |   |                 |
| > mechanisms that cause       |   |                   |   |                 |
| > increased cardiocyte        |   |                   |   |                 |
| > stiffness. This project     |   |                   |   |                 |
| > will examine changes in     |   |                   |   |                 |
| > calcium regulatory and      |   |                   |   |                 |
| > cytoskeletal proteins in    |   |                   |   |                 |
| > models of diastolic         |   |                   |   |                 |
| > congestive heart failure.   |   |                   |   |                 |
| >                             |   |                   |   |                 |
| > Role on Project: Principal  |   |                   |   |                 |
| > Investigator of Project 6;  |   |                   |   |                 |
| > Co-PI of Project 2;         |   |                   |   |                 |
| > Director of Animal Model    |   |                   |   |                 |
| > Core                        |   |                   |   |                 |
+-------------------------------+---+-------------------+---+-----------------+
|                               |   |                   |   |                 |
+-------------------------------+---+-------------------+---+-----------------+
| > 1 R01 HL089944-01A1         |   |                   |   |                 |
| > (LeWinter)                  |   |                   |   |                 |
| > 09/01/08-08/30/13 2.4       |   |                   |   |                 |
| > calendar (MUSC)             |   |                   |   |                 |
+-------------------------------+---+-------------------+---+-----------------+
| > NIH/NHLBI \$160,885/yr      |   |                   |   |                 |
+-------------------------------+---+-------------------+---+-----------------+
| > **Advanced Glycation        |   |                   |   |                 |
| > End-Products in Human       |   |                   |   |                 |
| > Myocardium**                |   |                   |   |                 |
+-------------------------------+---+-------------------+---+-----------------+
| > This clinically based R01   |   |                   |   |                 |
| > application seeks to        |   |                   |   |                 |
| > determine whether advanced  |   |                   |   |                 |
| > glycation end-products      |   |                   |   |                 |
| > contribute to heart         |   |                   |   |                 |
| > dysfunction in patients     |   |                   |   |                 |
| > with diabetes mellitus and  |   |                   |   |                 |
| > hypertension as well as     |   |                   |   |                 |
| > normal aging, all of which  |   |                   |   |                 |
| > are risks factors for the   |   |                   |   |                 |
| > development of heart        |   |                   |   |                 |
| > failure. Dr. Zile will      |   |                   |   |                 |
| > oversee and interpret       |   |                   |   |                 |
| > studies investigating       |   |                   |   |                 |
| > patient myocardial biopsies |   |                   |   |                 |
| > in *in vitro* experiments   |   |                   |   |                 |
| > to assess altered           |   |                   |   |                 |
| > cross-linking effects upon  |   |                   |   |                 |
| > passive stiffness and       |   |                   |   |                 |
| > myofilament contractile     |   |                   |   |                 |
| > properties. These results   |   |                   |   |                 |
| > will then be related to     |   |                   |   |                 |
| > findings of *in vivo* left  |   |                   |   |                 |
| > ventricular function.       |   |                   |   |                 |
| >                             |   |                   |   |                 |
| > Role on Project: Principal  |   |                   |   |                 |
| > Investigator- MUSC          |   |                   |   |                 |
| > subcontract                 |   |                   |   |                 |
+-------------------------------+---+-------------------+---+-----------------+
| **[OVERLAP]{.underline}**     |   |                   |   |                 |
+-------------------------------+---+-------------------+---+-----------------+
|                               |   |                   |   |                 |
+-------------------------------+---+-------------------+---+-----------------+
| > There is no overlap between |   |                   |   |                 |
| > the studies being proposed  |   |                   |   |                 |
| > in Dr. Spinale's Merit      |   |                   |   |                 |
| > Review application and any  |   |                   |   |                 |
| > of Dr. Zile's active or     |   |                   |   |                 |
| > completed grant support.    |   |                   |   |                 |
| > Specifically, Dr. Spinale   |   |                   |   |                 |
| > is examining the role of    |   |                   |   |                 |
| > MT1-MMP in pressure         |   |                   |   |                 |
| > overload. This has not been |   |                   |   |                 |
| > and is not a subject of Dr. |   |                   |   |                 |
| > Zile's investigation.       |   |                   |   |                 |
+-------------------------------+---+-------------------+---+-----------------+