TGFBeta Signaling in the Bladder Stroma

Vanderbilt University, Nashville TN

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Abstract

DESCRIPTION (provided by applicant): The long-term objective is to study intracellular networks of cytokine signaling which mediate bladder fibrosis, a major process affecting bladder function and in the pathogenesis of renal disease. A fibrotic bladder has three primary components: 1) elevated extracellular matrix deposition, 2) inflammatory infiltration, and 3) increased abundance of activated fibroblasts. Together, it leads to bladder non-compliance and potentially kidney damage. Since each of these components impact one another, it has been difficult to study one without the other factors influencing our interpretation. Members of the TGFbeta family and its receptors, expressed in both stroma and epithelium, are especially elevated in fibrosis. In an effort to understand the specific role of TGFbeta signaling in the bladder stroma, a fibroblast-specific conditional knockout mouse of the type II TGFbeta receptor gene (Tgfbr2) was generated. The conditional knockout mice display hypercellular stroma in many tissues including the prostate, mammary gland, and pancreas. Interestingly the conditional knockout mouse displays bladder stromal hyperplasia in the male, but not the female mice of the same genotype. Together with known instances of androgen and estrogen signaling crosstalk with the TGFbeta signaling actions with regard to cell proliferation in various tissues, we hypothesize that estrogens and androgens play a role in bladder stromal hyperplasia in a TGFbeta-dependent manner. The androgen receptor is expressed early in bladder development and both estrogen receptor isoforms are expressed in the developing and adult bladder. The fibroblast conditional Tgfbr2 knockout mouse model and tissue recombination studies will be used to: 1) Characterize the role of estrogen in TGFbeta signaling on the mature bladder stroma and 2) Determine stromal TGFbeta signaling mechanisms involved in bladder development. Studying the function downstream targets, and regulation of TGFbeta in the context of differential estrogen or androgen signaling in vivo will allow a mechanistic understanding of an important component of bladder fibrosis. Results from these studies are directly relevant to potential non-invasive strategies in treating one of the most common pathologies of the bladder.