The goal of my research is to solve clinical problems that l see in my urologic practice. Bladder dysfunction is one such problem. Under the mentorship of Dr. Gerald Cunha, a recognized leader in epithelial- mesenchymal cell-cell interactions, l hope to gain the expertise to become an independent scientific investigator. Dr. Cunha's previous work has focused primarily on the prostate, uterus and breast. With my previous experience in bladder research, on my return to UCSF after my pediatric urologic fellowship, it seemed natural to connect with an established investigator who could further guide my scientific development. In essence, this proposal is a natural extension of Dr. Cunha's work in the urogenital tract, applying established and accepted techniques to a previously neglected organ, the urinary bladder. The environment of Dr. Cunha's laboratory is conducive to studying cell-cell interactions in the bladder with expertise existing in all aspects of the proposed project including tissue recombination techniques, growth factors, immunocytochemistry and molecular biology. Most Importantly, the laboratory under Dr. Cunha's leadership has an excellent comradeship, nurturing a number of graduate students and postdoctoral fellows in their academic training. Hypothesis: * This proposal is based upon the hypothesis that normal bladder cell growth and differentiation are regulated by smooth muscle-epithelial cell- cell interactions mediated by the local production and action of growth factors and/or other paracrine-acting mediators. * This hypothesis will be examined through pursuit of the following specific aims: 1) Determine the role of epithelial-mesenchymal interactions in development of bladder smooth muscle; 2) Determine the specificity of epithelial induction of bladder smooth muscle. The overall strategy for specific aim # 1 & 2 will be the examination of tissue recombinants consisting of bladder mesenchyme that has been separated from its associated epithelial layers by trypsin digestion before the onset of smooth muscle differentiation. Bladder mesenchyme will be grown in association with bladder urothelium and the resultant tissue recombinants will be analyzed for expression of smooth muscle. * Specific aim #3 will examine the hypothesis that a diffusable growth factor and/or other paracrine-acting mediator is the mechanism for smooth muscle induction. Strategies for this specific aim consist of the utilization of a bioassay in which embryonic bladder mesenchyme undergoes smooth muscle differentiation In response to known growth factors. Such a bioassay will permit the isolation of a smooth muscle inducing factor(s). * Effective therapies for bladder rehabilitation and reconstruction in patients with bladder pathology remain a clinical challenge. Information obtained from Specific Aims 1-3 will permit rational decisions concerning the construction of replacement tissues for the dysfunctional urinary bladder (specific aim #4). The long-term objective of this research is to develop effective strategies for the induction of bladder smooth muscle and for urinary tract rehabilitation by understanding the cellular and molecular mechanisms of cell-cell interactions in bladder development.
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