My main scientific interests have been in the biology of the genitourinary tract. Bladder Pain Syndrome/Interstitial Cystitis (BPS/IC) is a chronic inflammatory disease of the bladder wall. More than 100 years after first being described, the diagnosis of BPS/IC is still associated with controversy. Given the difficulties associated with the diagnosis of BPS/IC, it is not surprising that the etiology of this syndrome is poorly understood.
In vitro studies in my laboratory have been consistent with the possibility that BPS/IC may develop in response to noxious stimuli in the bladder lumen. Thus, lipoteichoic acid (LT-2), a cell wall component of the gram-positive bacterium Streptococcus faecalis, stimulated the proliferation rate of a subpopulation of basal uroepithelial cells with high proliferative potential (possibly stem cells), their progeny differentiated at a higher rate and displayed abnormal expression and cellular distribution of β1 integrins, and LT-2 required activation of iNOS and NFκB. Moreover, our studies provided evidence for altered proliferative ability of progenitors of urothelial cells in cell cultures isolated from patients with BPS/IC. These studies raised a number of questions: What are the mechanisms by which noxious stimuli in the bladder lumen may trigger abnormal function of the muscle and nerve tissue underlying the uroepithelium, causing pain and persistent urge to void? In addition, how is it possible that chronic symptoms similar to those characteristic of bacterial cystitis persist for years in patients with BPS/IC in whom no infectious agent is detected at the time of diagnosis? Based on emerging data from several laboratories, I postulated in a review that epigenetic reprogramming mechanisms in the bladder may provide an explanation for uroepithelial, mast cells and nerve cell abnormalities in BPS/IC, as well as propagation of this altered state in the absence of the signal that may have triggered it. Data supporting this hypothesis would provide a rationale for new diagnostic, treatment and dietary intervention options for BPS/IC.
My second scientific interest is dietary prevention of prostate cancer (PC). PC is the most commonly diagnosed cancer in North American men. Findings of latent or clinically insignificant PC occur in a large proportion, and at equal rates, in autopsy studies among men from Asian countries and the United States. In contrast, the incidence of clinically significant PC is an order of magnitude higher in the United States. Epidemiological studies suggest that this might be attributable to differences in environmental factors and life style, including nutrition. Aggressive PC is less prevalent among Asian men where the intake of soy products is very high. However, with Westernization and loss of traditional eating habits, the pattern of disease incidence is also changing in Asian men. On the basis of these findings, it has been postulated that phytoestrogens, including genistein, may have a preventive role in PC. Studies in my laboratory in a transgenic mouse model of prostate cancer (TRAMP mice), supported this hypothesis
Prostate cancer fatalities are rarely due to primary tumors, but rather to widespread metastatic disease. The preferential colonization of bone by prostatic adenocarcinomas has been attributed to the passage of prostate epithelial cells from the prostate to the spine via paravertebral blood vessels. However, molecular mechanisms that facilitate retention of metastatic cells in bone and, their subsequent unrestricted proliferation, are poorly understood. In my laboratory, in vitro studies in cell cultures isolated from the human prostate and in vivo studies in the transgenic mouse model of prostate cancer focused on cell adhesion-mediated molecular mechanisms that: (i) May underlie progression of slow growing prostate tumors to metastatic growth; and that (ii) May be the target of preventive strategies that delay progression of indolent prostate tumors to metastatic growth.
In the past few years, in collaborative studies with Harry W. Schroeder, Jr., my interests have expanded to the link between natural protection against infectious agents and D(H) gene conservation.
