These investigators were selected by the present Steering Committee based on external review. The focus of these two Developmental Research/P&F projects was on the effects of estrogen on urethral and bladder functions. These young investigators benefited from the Core Facility and Educational Enrichment Program of the O’Brien Research Center and developed their expertise and skill for independent research in their selected topics with mentoring from senior investigators. Two of the P&F projects that our O’Brien Center had in the last funding period led to independent grants (RO1 & R21) and others are on the way to achieving their goals of obtaining independent funding.
Project #1 entitled “Urethral function in females: A Role for estrogen” is from Shaohua Chang, Ph.D., a Senior Research Investigator in the Division of Urology, Department of Surgery, School of Medicine, U of Penn. This proposal will focus on the downstream molecular/biochemical pathway leading to smooth muscle contraction in response to estrogen depletion and supplementation. The hypothesis is that estrogen regulates urethral smooth muscle via the following pathways, RhoA → Rho-kinase → myosin phosphatase → MLC20 phosphorylation → urethral smooth muscle tone (urethral function). The proposal will investigate how estrogen regulates RhoA/Rho-kinase pathway and whether the manipulation of RhoA/Rho-kinase pathway can improve the urethral smooth muscle tone which is altered by estrogen depletion.
Project #2 entitled “Effects of estrogen on female urethral obstruction” is from Gina M. Northington, M.D., Ph.D., an Assistant Professor in the Section of Urogynecology, Department of OB-GYN at University of Pennsylvania. The goal of this pilot and feasibility project is to gather sufficient preliminary data to prepare a more detailed RO1 proposal, asking mechanistic questions related to the role of estrogen in the remodeling of the detrusor smooth muscle in PBOO. As proposed, female rabbits with partial bladder outlet obstruction will be utilized as a model for functional detrusor overactivity in women. The hypothesis is that PBOO in the female rabbit causes alterations in bladder function and contractility as a result of changes in smooth muscle and estrogen depletion potentiates these effects. It is further hypothesized that estrogen replacement may, in part, reverse the myopathology and functional changes associated with PBOO in a female animal.
Two new P&F grant proposal have been included from two investigators who are seeking funding to generate sufficient preliminary data to prepare competitive RO1 proposals. The Core Facility, Bladder Tissue Core and the interaction with senior investigators would help these investigators to address mechanistic problems related to their study problems. These projects were reviewed by outside reviewers and approved by the Steering Committee and the Internal Advisory Committee.
Funding for the 2nd year will be decided after reviewing the progress of these projects by the Steering Committee. After the two-year funding period, both of these P&F projects will seek support through individual NIH R01 grants.
Project #1 entitled “Role of M2 and M3 Receptor Internalization in Human Bladder Sensitivity to Cholinergic Stimulation” is from Alan S. Braverman, PhD, an Assistant Professor in the Department of Urology, Temple University School of Medicine. This proposal will focus on the determination of the density of cell surface and internal M2 and M3 receptors in the detrusor muscle and urothelium from a relatively large human bladder tissue bank of over 40 specimens and newly procured human bladders from organ transplant donors.
Project #2 entitled “Cellular and molecular mechanism underlying co-morbidity between lower urinary tract symptoms and erectile dysfunction” is from Allen D. Seftel, M.D., a Professor and Chairman of the Division of Urology, Cooper University Hospital. The overall objective of this proposal is to elucidate the cellular and molecular mechanisms that underlie co-morbidity of LUTS and ED.