***Basic Research in Interstitial Cystitis: 1^st^ Annual Investigators'
Meeting***

**October 20th -- 21st, 2004**

**Sheraton 4 Points Washington DC**

**Post-Meeting Summary of 1^st^ Annual IC Basic Science Investigators
Meeting Panel Discussions: Advances, Needs and Future Directions**

**Session I: Pelvic Pain and Neurobiology**

**Chair: Margaret A.Vizzard, Ph.D.**

**Summary of Key Points:** Discussion of ICOS press release that
indicated that resiniferatoxin (RTX) clinical trial on patients with
interstitial cystitis (IC) was stopped due to a lack of benefit. It was
contributed that patient selection may have been a key factor in that
end-stage IC patients were recruited and it was also contributed that
the vehicle selected to deliver the RTX may have been the problem. Thus,
the consensus was that there is still strong evidence that implicates
C-fiber bladder afferents in contributing to pain, urgency, frequency
and incontinence and that ICOS has not abandoned this emphasis but is
currently restructuring the approach.

Several presentations dealt with cross sensitization of pelvic viscera,
as IC patients often present with pain in viscera in addition to the
urinary bladder. One mechanism that may account for cross sensitization
was suggested by both Dr. Pezzone and Wesselmann and concerned
dichotomizing afferents. In addition to this suggestion, the possibility
of a paracrine mechanism at the level of the dorsal root ganglion was
suggested.

**Needs/Future Directions:**

-   It was concluded that a paracrine mechanism may be another mechanism
    to account for cross sensitization (viscera pain with bladder pain).
    Importantly, additional research needs to focus on this area.

-   There was considerable interest in the presentations that discussed
    referred somatic pain sites in individuals with IC. Whereas referral
    of somatic pain to the same dermatome as that innervating the
    urinary bladder is not surprising, other referred pain (i.e., hand,
    arm) is more puzzling.

-   It was concluded that additional pain-site mapping studies would be
    useful and may be helpful in grouping different populations of
    IC/PBS/CPPS patients.

-   A discussion of rat models compared to mouse models was initiated
    and the question was posed as to whether micturition reflexes in
    rats and mice are, in fact, the same. While most people seemed to
    believe this to be the case, definitive comparative studies have not
    been performed. It was also discussed that the mouse presents unique
    difficulties when performing cystometry that need to be overcome for
    successful recordings. What are the differences between mice and
    rats (as IC/PBS/CPPS models, etc)?

**Session II: Inflammation and Immunobiology**

**Chair: David J. Klumpp, Ph.D.**

**Needs/Future Directions:**

-   The discussion revealed the opinion that the immunobiology of the
    bladder is an understudied area. Indeed, many classic immunology
    experiments have never been performed for the bladder.

-   Additional areas in need of further attention include: (1) standard
    definition of glomerulations and information on the frequency of
    glomerulations are lacking, (2) no accepted guidelines for
    standardization of hydrodistention methodologies, (3) the importance
    of mucosal immunity to bladder function, and (4) the diversity of
    definitions/growth conditions for "urothelial" cells (major issue).

-   This latter topic -- urothelial cell diversity -- was considered an
    especially important issue facing IC basic research. The diversity
    of ways currently used to grow (culture) urothelial cells and even
    the definition of urothelial cells varies from lab to lab. There is
    no standardized way to identify/characterize urothelial cells. This
    is an area that would benefit from a "Consensus Conference".

-   In addition, the similarities and differences between epithelial
    cells from different organs, how to isolate them, how to grow them,
    and how they respond to similar treatments (e.g. response to NF-kb)
    should also be addressed. This conference may also involve a
    practical comparison of urothelial cells from different labs
    currently active in IC basic research.

**Session III: Urothelial Cell Biology and Barrier Function**

**Chair: Jennifer Southgate, Ph.D.**

**Summary of Key Points:** This section included presentations on
urothelial differentiation and function, highlighting the varied roles
of the urothelium in urinary barrier function, mechanosensation, neuro-
and immuno-modulation. Cell culture systems again featured as a
prominent issue and it was clear that much remains to be understood
about the basic biology and function of the normal tissue. Although many
parallels exist between urothelium and other epithelial tissues in terms
of growth/differentiation, urothelium also has unique molecular,
cellular and functional features that are very relevant to understanding
its pathobiology.

**Needs/Future Directions:**

-   Relevant areas of urothelial biology in need of further research
    efforts include:

    1.  wound response/repair

    2.  differentiation (regulation thereof and relationship to
        function)

    3.  urothelial:stromal cell interactions (reciprocal communication
        between both compartments)

    4.  identification of stem/progenitor cells (note that urothelial
        heterogeneity within the urinary tract remains an issue)

    5.  interactions of urothelial cells with the immune and purinergic
        systems

    6.  determining importance/relevance of glycosaminoglycans in
        differentiated human urothelium.

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-   It was proposed that in culture, normal urothelial cells retain the
    potential to express the fully differentiated urothelial phenotype
    if provided with the appropriate environmental cues (growth factors
    etc), but that most culture systems represent urothelial cells with
    more proliferative and less well-differentiated characteristics.
    Differences in culture conditions between laboratories could account
    for differences in results and there is some call for consensus by
    identifying standardized urothelial cell culture systems and marker
    (gene/ antigen) panels for characterization.

**Session IV: Genetics, Genomics and Proteomics**

**Chair: Brian C. Liu, Ph.D.**

**Summary of Key Points:** Several key/outstanding questions raised:
What do we need in place to compare cell lineages?, how do we validate
cell culture/growth approaches?, how do murine IC models differ (from
each other and from lab to lab)?

**Needs/Future Directions:**

-   The fact that there remains a lack of a case definition for IC was
    raised.

-   More focus on basic science in IC (e.g. urothelial-muscle
    communication, EM on mast cells, etc) is needed.

-   Standard IC mouse models are needed -- now many exist (e.g. BCG,
    CYS, etc) -- these all have limitations.

-   There remains a need to translate basic science findings to
    pathologists/clinicians.

-   A routine mast cell analysis is needed for IC (to rule in or out
    inflammation).

-   Also, the role of inflammation in IC is unclear.

**Session V: Etiology, Diagnosis, and Treatment for IC**

**Chair: Jordan Dimitrakov, M.D., Ph.D.**

Recommendations for the next meeting were initially discussed, including
suggestions to (1) invite some epidemiologists and psychologists with
specific interest in IC basic research (e.g. Dr. Reeves from the CDC);
(2) ask researchers to suggest names of researchers in other basic
researchers area they would like to see at the meeting (probably by
e-mailing them 3 months before the meeting); (3) have an expanded poster
session where graduate students and post-docs can present, similar to
the session of the newly-found Society for Infection and Inflammation in
Urology; (4) Dr. Dimitrakov suggested we develop a structured
questionnaire that we can send to participants from this year\'s meeting
and get their specific feedback and possibly put together an article
which will give an overview of the future directions in IC research.