Mechanisms of Cytokine Induced Lower Urinary Track Pathology

Baylor College of Medicine hosted a Symposium, Wednesday, Oct. 9: Pathobiology of Prostatic Hyperplasia and Lower Urinary Tract Symptoms in Aging Men.

Presentations were made by Drs. Michael Ittmann, David Rowley, Li Xin and Keith Chan.

Keynote Speaker, Dr. Jill Macoska, professor of Biological Sciences from the University of Massachusetts presented her work: "Fibroblast-Mediated Prostate Pathobiology."

The goal of this proposal is to characterize the mechanisms by which cellular senescence can promote the development of benign prostatic hyperplasia and via paracrine effects and/or mechanical obstruction induce changes in the urinary bladder.

Michael Ittmann, M.D., Ph.D.
Professor
Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX
Email: mittmann@bcm.edu

David Rowley, Ph.D.
Professor
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
Email: drowley@bcm.edu

Keith Chan, Ph.D.
Assistant Professor
Department of Urology, Baylor College of Medicine, Houston, TX
Email: kc1@bcm.edu

Li Xin, Ph.D.
Assistant Professor
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
Email: xin@bcm.edu

We have previously shown that two cytokines induced by epithelial senescence (IL-1α and IL-8) are increased in BPH and are correlated with BPH severity. A number of other cytokines are upregulated during epithelial senescence. The goals of this Aim are 1) to determine if these cytokines are upregulated in BPH epithelium and if their levels correlate with levels of other senescence markers and 2) characterize the cytokines and growth factors upregulated in BPH epithelium and stroma adjacent to this epithelium (periacinar stroma). We will use laser capture and Q-RT-PCR for specific cytokines to quantitate expression of specific senescence induced mRNAs in normal TZ and BPH epithelium. In addition, we will carry out studies using expression microarray analysis to identify the entire repertoire of cytokines and growth factors with increased expression in BPH epithelium. This Aim we will both test our hypothesis regarding the role of epithelial senescence in BPH and derive a comprehensive list of potentially important cytokines/growth factors in BPH/LUTS.

Based on our data it is almost certain that multiple cytokines contribute to the phenotype of BPH/LUTS. In this Aim we will explore the utility of using several highly tractable models developed by our group to examine the impact of specific cytokines on cell growth and cellular phenotype in the context of epithelial/stromal interactions. Given the number of potential cytokines and growth factors that play a role it is essential to have such systems since building transgenic mice for all relevant factors is impractical. We will use a novel three dimensional (3D) cell culture system, the differential reactive stroma model and the prostate reconstitution system to examine key interactions driving growth of epithelial and stromal cells.

In this Aim we will take advantage of a prostate promoter-specific transgenic mouse model generated by the Ittmann lab, to examine the possible role of inflammatory cytokines from the prostate gland in inducing LUTS and urothelial alterations in urinary bladder. We will examine the spatial and temporal histological analysis of pathological changes in the bladder urothelium of mouse models. We will then characterize the changes in stem, progenitor and differentiated cell markers in associated to cytokine-induced inflammatory condition in bladder urothelium. Finally, we will examine the interaction of bladder urothelial cell subpopulations with sensory receptors known to be involved in LUTS.