Major laboratory research projects in the Department of Urology include:
Urinary Bladder Muscarinic Receptor Subtypes. NIH R01 DK43333. Total award, direct costs: $997,776, 2000-2004.
The long range goals of this project are to the define the role of the different muscarinic receptor subtypes in normal bladder function and to determine changes that occur with dysfunction. We have previously demonstrated changes in the role of M2 and M3 muscarinic receptor subtypes in bladder hypertrophy and neurologic dysfunction in both animal and human bladders. The overarching hypothesis of this proposal is that it is not only a relative contribution of each subtype that changes, but the pathways of signal transduction mediating the muscarinic receptor responses that becomes altered as well. We will test this hypothesis in several systems. The use of knockout (KO) mice allows for isolation of either the M2-mediated or M3-mediated response and therefore to more fully characterize signal transduction for each individual receptor subtype. We have used the rat as a model for hypertrophy and denervation, and will determine the changes in signal transduction pathways that mediate our observed changes in M2-mediated and M3-mediated contraction. We will also use human bladder from organ transplant donors and correlate alterations in signal transduction with markers of bladder hypertrophy to gain insight into biochemical changes that may be mediating the clinical changes in bladder function. Finally, we will use micro arrays to describe changes at the gene transcript level that contribute to changes in bladder function.
To test this hypothesis, we performed the following specific aims:
Residents were involved in performing experiments, collecting data and presenting research.
Gallbladder Muscarinic Receptors in Acute Cholecystitis. NIH R01 DK58261 - Consortium subcontract from Medical College of Virginia. Total award, direct costs of Temple subcontract, $586,950, 2001-2006.
Specific aims are:
a) To determine the changes in gallbladder smooth muscle muscarinic receptor subtype following initiation of acute inflammation in the gallbladder using the common bile duct ligation model in the guinea pig. These studies will test the hypothesis that acute inflammation alters the primary muscarinic receptor subtype that mediates gallbladder contraction from M3 to M2.
b) To determine the changes that occur in contractile signal transduction mechanisms following initiation of acute inflammation in the gallbladder. These studies will test the hypothesis that acute gallbladder inflammation shifts muscarinic receptor subtypes through a change in the contractile signal transduction mechanisms.
d) To determine the effects of exogenous inflammatory mediators on gallbladder contractile signal transduction. These studies will test the hypothesis that specific inflammatory mediators decrease gallbladder contractility by decreasing prejunctional acetylcholine release and altering the prejunctional muscarinic receptor subtypes that modulate transmitter release.
Feasibility of Intercostal Nerve Transfer for Urinary Bladder Reinnervation: A prelude for Restoration of Bladder Emptying with Functional Electrical Stimulation. Shriners Hospital for Children. Total direct costs, $565,859, 2001-2004.
The overall goal of this project is to use a canine model to determine the feasibility of somatic nerve transfer for reinnervation of the urinary bladder. Bladder emptying will be induced with functional electrical stimulation (FES) of the transferred somatic nerves. This proposal is designed to achieve the following specific aims:
These studies will test the following specific hypotheses:
Effect of Test Compounds on Outlet Obstruction Induced Detrusor Overactivity in the Rat. AstraZeneca Pharmaceuticals, Inc. $165,000, 2004-2005.
Awake cystometry of rats subject to bladder outlet obstruction demonstrates increased micturition pressure and spontaneous bladder contractions. These cystometric parameters can be inhibited by several classes of drugs including potassium channel agonists, muscarinic receptor antagonists and perhaps 5-HT1A receptor antagonists, as well as neurokinin receptor antagonists. Four different compounds will be tested in this model in a blinded fashion on both obstructed and sham operated controls.
Signal Transduction Mechanisms Mediating M2 and M3 Contraction of the Urinary Bladder. $50,000, 2005.
The studies proposed in this application will meet the goals of this grant program because they will determine the second messenger pathways activated by the individual M2 and M3 muscarinic receptor subtypes that result in bladder contraction.
Effects of Sera from Obese and Lean Patients on the Progression of Prostate Tumors. $25,000 CaPCURE grant, $15,000 RTOG, $10,000. Temple Research Incentive Grant, $50,000. J. Mydlo, PI; NIH Health Disparities Research Grant, Raul Dela Cadena, P.I.
Based on preliminary data, we theorize that obese patients have increased growth factors in their sera to increase production in their adipose tissues, as well as have decreased immune function. The synergy of increased stimulation due to growth factors and decreased inhibition due to an impaired immune system may allow tumors to progress at a more rapid rate in obese patients compared to lean patients.
Specific aims are:
a) To assess the levels of fibroblast growth factor two (FGF-2) and vascular endothelial cell growth factor (VEGF) in the sera of lean and obese patients.
b) To assess macrophage and killer cell activity in sera from lean and obese patients.
c) To assess prostate tumor progression in tumors implanted in genetically lean and obese Zucker rats.
We have had several residents as well as medical students participate in this project and have already submitted a manuscript and several grants based on our preliminary results.
Chronic Prostatitis Clinical Research Center. NIH R01 DK5734. Total direct costs, $791,290, 1997-2005.
This study is designed to spawn an interactive research network of clinical centers to validate survey and laboratory diagnostic tools which can be used in standardized clinical study protocols involving men with category III prostatitis. This is a proposal to be chosen as one of the clinical centers which will be carrying out these studies. Temple University is particularly qualified to do so for a number of reasons. We have extensive experience with inflammatory disease of the lower urinary tract, especially Interstitial Cystitis (IC), and were one of the participating centers in the IC Database (ICDB) study.
This study was funded in 1997 and to date we are one of originally six centers, and now ten centers that have recruited over 450 men for a longitudinal cohort study, and over 190 men for a randomized clinical treatment trial. We have been involved in the development of the NIH-Chronic Prostatitis Symptom Index (NIH-CPSI) which was published in the Journal of Urology in 1999. Dr. Pontari presented the epidemiological findings of this study, comparing the men with chronic prostatitis and asymptomatic age matched controls at the 2002 annual AUA meeting, along with a basic science project comparing levels of nerve growth factor in the seminal plasma of these two groups. Dr. Pontari and Ruggieri have been involved in this study. Residents have not participated in the study to date.
Applied Methods for Evaluation of Interstitial Cystitis. NIH R01 DK059601-04.
This project involves the comparison of the past history and epidemiological risk factors in patients with interstitial cystitis and chronic prostatitis/chronic pelvic pain syndrome.
William Jaffe, MD
Department of Urology
Temple University School of Medicine
Suite 330, Zone C
Philadelphia, PA 19140