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department of urology

Research Programs

 

Major laboratory research projects in the Department of Urology include:

 

Urinary Bladder Muscarinic Receptor Subtypes

 

Urinary Bladder Muscarinic Receptor Subtypes.  NIH R01 DK43333.  Total award, direct costs:  $997,776, 2000-2004.

 

Principal Investigator:

Michael R. Ruggieri, Sr., PhD

 

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:

  1. Used inhibitors of protein kinases and phospholipases to understand their roles in transducing the muscarinic receptor mediated contractile signal in M2, M3 and combined M2/M3 receptor knockout mice.
  2. Determined the role of these enzymes in the M2 and M3 muscarinic receptor-mediated contractile signal transduction pathways of the rat bladder.
  3. Used human bladder tissue obtained from brain dead organ transplant donors, determined the role of these enzymes in the M2 and M3 muscarinic receptor-mediated contractile signal transduction pathways of the normal and hypertrophied human bladder.
  4. Using Affymetrix Genechip® arrays, we determined the differential gene transcript expression in the bladder resulting from denervation and hypertrophy in the rat and from M2, M3 and combined M2/M3 receptor knockout in the mouse.

Residents were involved in performing experiments, collecting data and presenting research.

 

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Gallbladder Muscarinic Receptors in Acute Cholecystitis

 

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.

 

Principal Investigator:

Michael R. Ruggieri, Sr., PhD

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.


c) To determine the changes in muscarinic autoreceptors that regulate acetylcholine release from intrinsic gallbladder cholinergic neurons following initiation of acute inflammation in the gallbladder. These studies will examine the hypothesis that the muscarinic autoreceptors (M1, M2 and M3) that regulate acetylcholine release from the intrinsic gallbladder cholinergic neurons are altered following acute gallbladder inflammation.

 

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.

 

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Feasibility of Intercostal Nerve Transfer for Urinary Bladder Reinnervation:  A Prelude for Restoration of Bladder Emptying with Functional Electrical Stimulation

 

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.

 

Principal Investigator:

Michael R. Ruggieri, Sr., PhD

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:


a) Bypass the bladder motor nerve transection with caudal nerves innervating the tail, achieving bladder emptying by FES with implanted electrodes to provide proof of concept for somatic nerve reinnervation of a visceral smooth muscle organ.


b) Develop and fabricate a totally implanted bladder nerve-stimulating system with telemetric control.


c) Implant the newly developed bladder nerve-stimulating system on the caudal nerves that have been used to bypass the bladder motor nerve transection to determine its feasibility for maintaining control of bladder function.


d) Determine whether caudal somatic nerve transfer can reinnervate the bladder if the nerve transfer surgery is performed at various time periods after the bladder nerve transection.

These studies will test the following specific hypotheses:


  • Neurorrhaphy of a caudal somatic nerve to the rhizotomized sacral bladder nerves results in reinnervation of the urinary bladder by the caudal somatic nerves.
  • The transferred caudal nerves can be stimulated to induce bladder emptying by FES of the transferred nerves via implanted electrodes.
  • A totally implanted bladder nerve stimulation system can induce bladder emptying via stimulation of the transferred caudal somatic nerves.
  • Somatic nerve transfer via a sural nerve graft may only be able to
    reinnervate the urinary bladder within a certain time window following
    bladder nerve transection.

The transferred intercostal nerves can be stimulated to induce bladder emptying by functional electrical stimulation (FES) of the transferred intercostal nerves via implanted electrodes.

Intercostal nerve transfer via a sural nerve graft may only be able to reinnervate the urinary bladder within a certain time window following bladder nerve transection. Residents are involved in canine surgery and grafting, and collecting data.

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Effect of Test Compounds on Outlet Obstruction Induced Detrusor Overactivity in the Rat

 

Effect of Test Compounds on Outlet Obstruction Induced Detrusor Overactivity in the Rat.  AstraZeneca Pharmaceuticals, Inc.  $165,000, 2004-2005.

 

Principal Investigator:

Michael R. Ruggieri, Sr., PhD

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.

 

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Signal Transduction Mechanisms Mediating M2 and M3 Contraction of the Urinary Bladder

 

Signal Transduction Mechanisms Mediating M2 and M3 Contraction of the Urinary Bladder.  $50,000, 2005.

 

Principal Investigator:

Alan S. Braverman, PhD

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.


Knockout mice have proven useful in determining the distinct roles of individual receptor subtypes in bladder contraction. In the M3 knockout mouse bladder, maximal carbachol induced contraction is inhibited by 95%, while in the M2 knockout mouse the potency of carbachol for inducing contraction is significantly increased approximately two-fold . In the combined M2 and M3 knockout mouse, bladder contraction in response to carbachol is completely inhibited . Thus, the above results demonstrate that bladder contraction is mediated by both the M2 and M3 muscarinic receptor subtypes. We have shown in the hypertrophied rat and many human bladder specimens that the M2 receptor may have a greater role in mediating contraction than in the mouse bladder, although rat bladder contraction seems to be mediated by both the M2 and M3 receptor subtypes acting in concert. In the M3 knockout mouse stomach fundus, the carbachol induced maximal contraction is inhibited by about 50%. Thus, the contractile roles and the signal transduction pathways activated by the individual M2 and M3 receptor subtypes in human and rat urinary bladder may be more similar to the mouse stomach fundus than the mouse urinary bladder.

 

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Effects of Sera from Obese and Lean Patients on the Progression of Prostate Tumors

 

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.

 

Principal Investigators:

Raul Dela Cadena, MD

Jack Mydlo, MD

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.

 

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Chronic Prostatitis Clinical Research Center

 

Chronic Prostatitis Clinical Research Center.  NIH R01 DK5734.  Total direct costs, $791,290, 1997-2005.

 

Principal Investigator:

Michel A. Pontari, MD

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.

 

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Applied Methods for Evaluation of Interstitial Cystitis

 

Applied Methods for Evaluation of Interstitial Cystitis.  NIH R01 DK059601-04.

 

Co-Principal Investigator:

Michel A. Pontari, MD

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.

 

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New Research Programs

 

Jack Mydlo, MD

  1. Health Disparities Program.  A pilot study to examine levels of fibroblast growth factor (FGF-2) and vascular endothelial cell growth factor (VEGF) in relation to changes in BMI after bariatric surgery.
  2. Combination therapies for erectile dysfunction in which monotherapy is sub-optimal.

Michel A. Pontari, MD

  1. Functional brain imaging of changes in CNS function after cholinergic therapy in patients with overactive bladder.
  2. Investigation of antiproliferative factor (APF) levels in the urine of patients diagnosed with interstitial cystitis (IC) by mass spectroscopy.
  3. Prospective observational registry and patient surgery of the management of men with symptomatic benign prostate hyperplasia (BPH):  BPH registry and patient survey.

William Jaffe, MD

  1. Outcome of stress incontinence in obese women undergoing bariatric reduction surgery.
  2. Outcome of bladder detrussor instability in women on alpha blockers.
  3. Laser prostatectomy as outpatient treatment for BPH.

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