Active Grants

Funding Agency:

NIDDK

Principal Investigator:

William Ricke, PhD

Lab:

Ricke Lab

Division:

Urology

Project Summary:

The Specific Aims of the UW-Madison George M. O’Brien Urology Cooperative Research Center are: 1. To investigate molecular and cellular biological mechanisms driving fibrosis in the prostates of mice and men; and 2. To investigate the relationship of hormonal, developmental, metabolic, and inflammatory processes in development of fibrosis associated with lower urinary tract dysfunction tract using functional urological testing. Fibrosis is commonly observed in the prostates of men with Benign Prostatic Hyperplasia (BPH) and Lower Urinary Tract Symptoms (LUTS). Fundamental causes of prostatic fibrosis and the relationship of prostatic fibrosis to LUTS remain unclear. The overall goals of this Center are to critically investigate fundamental mechanisms that underlie development of prostatic fibrosis and to determine the relationship between benign prostatic disease and lower urinary tract dysfunction. Our center consists of four research projects, and each incorporates unique models of benign prostatic disease in mice and analysis of tissues from BPH patients to address the objectives of the Center. The Administrative Core will provide oversight and alignment of projects. The Administrative Core will also manage the Educational Enrichment Program
and Opportunity Pool. The Biomedical Research Core will provide project leaders and other investigators with the resources in mouse urinary function testing and histology to achieve the goals of the research. The Biomedical Core, in cooperation with the NIDDK and other groups, will also develop a robust database to make results and pertinent information generated by the Center and elsewhere readily accessible. This is a new venture and one that is of substantial importance to the urological research community. The long-range goal is to achieve an individualized and mechanistic understanding of LUTS pathophysiology and thereby refine patient selection for existing therapies. We will leverage our extensive institutional resources to develop an outstanding educational enrichment program that incorporates new researchers from all levels into urologic research. By meeting these objectives, this Center will make significant progress toward understanding mechanisms underlying LUTS, resulting in new mechanistically-targeted therapeutic options.

Funding Agency:

NIH/NIDDK

Principal Investigator:

Dr. Petra Popovics

Project Summary:

The overarching goal of Dr. Popovics’ proposal is to acquire technical and professional skills to become an independent investigator at a leading academic institution and develop a research program deciphering the molecular mechanism of inflammation induced prostatic tissue remodeling and fibrosis. This will be pursued through a scientific project that will determine whether osteopontin, a pro-fibrotic secreted phosphoprotein, stimulates prostatic inflammation, fibrosis, and lower urinary tract dysfunction.

Dr. Popovics’ training is focused on four key areas: 1) functional testing of mouse urinary function, 2) developing biomedical engineering technologies to study prostatic fibrosis in vitro, 3) testing and further developing animal models to study inflammation-induced prostatic fibrosis and its consequences on urinary function and, 4) gaining essential training in immune-regulated tissue remodeling. UW-Madison and the UW O`Brien Center for Benign Urology Research presents a unique environment for the proposed research and career development activities. This includes seminars presented by local and national leaders of the field, career development activities of several institutes across campus, clinical training of the Department of Urology, and specific training in immunopathology and tissue engineering.

Lower urinary tract symptoms (LUTS) secondary to benign prostatic diseases deteriorate the quality of life as men age. The treatment of male LUTS costs $4 billion annually and presents an economic burden on our healthcare system. It has been recently identified that prostatic inflammation and fibrosis are associated with LUTS, but the exact contribution of these mechanism to urinary dysfunction is unknown. Medical therapies targeting inflammation and fibrosis could enhance drug development and provide novel molecular targets for LUTS. Based on Dr. Popovics’ preliminary studies, she hypothesizes that inflammation-induced osteopontin levels stimulate prostatic fibrosis and lower urinary tract dysfunction (LUTD). The hypothesis will be tested by the following aims: 1)  Test the hypothesis that OPN is required for inflammation-induced prostatic collagen accumulation and LUTD, 2)  Test the hypothesis that OPN induces prostatic fibrosis.

The proposal will provide novel detection of collagen deposition, 3D in vitro and in vivo models of prostatic fibrosis. It will also decipher the specific role of inflammation-induced prostatic fibrosis in lower urinary tract dysfunction. This will be achieved by capitalizing on recently established prostatic models and state-of-the-art urinary physiological tests uniquely available at the UW-Madison.

Funding Agency:

NIA

Principal Investigator:

Dr. Teresa Liu

Project Summary:

Dr. Liu’s overall career goal is to become an independent investigator and leader in an aging related field focused on urologic diseases, especially lower urinary tract dysfunction (LUTD). Benign prostatic hyperplasia (BPH) is a disease that primarily affects aging men and manifests as urinary dysfunction. However, the etiology of the disease is complex and multifactorial and the impact of aging on the hormone environment is often not considered in current research.

The overarching goal of Dr. Liu’s work is to examine the effects of aging on sex steroid hormones that contribute to the development of disease and identify biomarkers relevant to disease progression and treatment efficacy. The goal of this K01 career development proposal is to provide Dr. Liu with the research experience and training needed to become an independent investigator and leader in the field. Dr. Liu’s training will be targeted to three key areas: 1) molecular modeling of aging and disease, 2) identification and analysis of peripheral biomarkers, and 3) epigenetic modifiers of the aging steroid hormone environment.

This research experience combined with the mentoring from leading experts at the University of Wisconsin – Madison will uniquely position Dr. Liu for a successful independent research career. Research: Benign prostatic hyperplasia (BPH) impacts 50% of men in their 50s but dramatically increases to 90% of men in their 80s with annual treatment costs $4 billion. One consequence of aging in males is altered steroid hormone synthesis and metabolism that leads to elevated levels of circulating estrogens. Estrogen signaling through estrogen receptors (ER) within the prostate regulate prostate tissue homeostasis with ERα associated with proliferation and ERβ with apoptosis. Current BPH treatments target the biosynthesis of androgens with little consideration for androgen conversion to ER ligands. Dr. Liu hypothesizes that selective ER modulators (SERMs) can reestablish ERα:ERβ homeostasis through ERβ activation and reverse the impact of ERα-mediated proliferation on BPH progression in the aging male. The critical elements of this hypothesis will be tested in the following specific aims: Aim 1: Determine the impact of age-related changes in steroidogenic enzymes required for ERβ ligand production on prostate proliferation in vitro and in vivo. Aim 2: Examine the effect of aging on the epigenetic regulation of steroid hormone metabolism and activity. Aim 3: Evaluate the effectiveness of SERMs to limit hyperplasia in the aging prostate. The work proposed in these aims is designed to identify potential peripheral biomarkers to aid in assessing and stratifying BPH patients with age-associated hormone driven hyperplasia. This will allow for the development of novel combination pharmacotherapies that would enhance the clinical efficacy of current drug treatments.

Funding Agency:

NIDDK

Principal Investigator:

Dr. William Ricke

Project Summary:

Healthcare costs for lower urinary tract symptoms (LUTS) ascribed to benign prostatic hyperplasia (BPH) are in the billions of dollars annually. Therapies for BPH/LUTS target smooth muscle contractility with α-blockers or hyperplasia with 5α-reductase inhibitors. Although these therapies can be medicinal, they are not effective/durable for all; this leaves millions of men in the US needing more effective therapies. The standard of medical care for BPH/LUTS currently over-treats this patient population, in part due to a poor understanding of etiology and progression. There is an apparent need to define what BPH represents in patient populations as well as to identify the true anatomic, cellular, and molecular causes of the disease. This may elucidate the true causes in development and progression of the disease as well as institute effective therapies. The overarching goal of the O’Brien Center for Benign Urology Research is to identify the mechanisms that result in lower urinary tract dysfunction and prostate-related LUTS. Previous studies have demonstrated prostatic collagen deposition coincident with prostate stiffness, LUTS, and failed medical treatment supporting the concept that BPH/LUTS is, in part, a fibrotic disease. However, this brings up a translational challenge because treatment of prostatic fibrosis cannot occur until cellular and molecular pathways have been identified. As such, the goal is to identify the anatomical, cellular, and molecular origins of prostate fibrosis in men with BPH/LUTS. Recently, estrogens, specifically signaling through estrogen receptor (ER)α, was discovered to be necessary for the development of prostatic fibrosis and LUTD in mice. Although, multiple stromal and epithelial cells express ERα, a subpopulation of ERα positive prostatic fibroblasts and/or smooth muscle cells could be responsible for increased collagen deposition. These cells are sensitive to estrogens and produce large amounts of collagen in vitro and in vivo.

Aim 1 will address the ER molecular mechanism of action in the transcription of Col1a1 by determining if classical or non-classical ER signaling is necessary. Next, collagen accumulation has been linked with BPH/LUTS, but it is uncertain if collagen/fibrosis acts independently or in collaboration with prostate hyperplasia; Aim 2 will test the hypothesis that gain of collagen function promotes LUTD independent of prostate hyperplasia. Clinical translation of our findings is a goal of the center; Aim 3 will test the hypothesis that clinically relevant antifibrotics are effective in the treatment of prostatic fibrosis. Lastly, stratification of men with fibrotic prostates is imperative to increase treatment efficacy. To address this challenge, advanced and novel collagen MR imaging techniques will be used to assess whether prostatic fibrosis can be identified in preclinical models. By establishing cellular and molecular mechanistic connections between fibrosis and BPH/LUTS as well as preclinical testing and patient stratification our collaborative and synergistic research, Project 1 will lay the groundwork for impactful discoveries that elucidate an important etiology of BPH/LUTS and may ultimately translate into the clinic.

Funding Agency:

NIDDK

Principal Investigator:

Dr. William Ricke

Project Summary:

The Administrative Core (Core A), has an overall mission to coordinate and successfully manage the UW- Madison O’Brien Research Center including UM-Boston and UT-Southwestern and lead benign urology research into the future. The overarching goal of the O’Brien Center for Benign Urology Research is to identify mechanisms that result in lower urinary tract dysfunction (LUTD) that result in benign prostatic hyperplasia (BPH) related lower urinary tract symptoms (LUTS). Criteria for successful completion are defined by the RFA 18-029 and include performing and disseminating outstanding benign urologic research, provide highly needed resources for the field, and provide outstanding educational enrichment while promoting the next generation of benign urology researchers. The Center targets new and exciting mechanisms of LUTD namely prostate fibrosis and translates it to clinically relevant therapeutics and biomarkers for patient stratification. BPH/LUTS can be life-threatening, affect quality of life, and is a costly disease, which NIDDK wants eradicate. Core A will achieve these goals by providing outstanding leadership, vision, and efficiency in the overarching administrative duties. The organization structure and leadership of Core A includes two outstanding investigators with recognized and complementary abilities in leading research groups and training programs. Dr. Ricke continues to serve as Core A director and will assume primary responsibility for day to day management and oversight of Core A. He will also be responsible for obtaining and managing the Opportunity Pool and maintain extensive interactions within the biomedical community.

Dr. Vezina will serve as Associate Director for Core A and will direct the Educational Enrichment Program. Core A will interact with members of its external advisory board (EAB) and internal advisory board (IAB) on a semi-annual basis. All members or associated members of the center will be invited to partake in center functions including seminars, retreats, business meetings, and other special events. Drs. Ricke and Vezina meet with the NIDDK Executive Steering committee (ESC) and External Expert Panel (EEP) at NIDDK’s annual reverse site visit (see letter of reference Mark Nelson, PhD, ESC Chair). Their leadership and experience will allow us to promote interactions between our Center Projects, Core B, as well as other centers (U54, P20, K12) through: communication, collaboration, and coordination. Further interactions and data dissemination will occur in conjunction with the NIDDK’s O’Brien Center Interaction core, NIDDK program officials, American Urological Association Office of Research, scientific societies, and other venues. As directed by NIDDK, the benign urology research community has a viable focal point–The O’Brien Centers–in which to centralize ideas, research, resources, training, provide consensus, and offer a unified voice. The O’Brien Centers are more than the sum of parts, rather they provide leadership, synergize with researchers, and provide to the urology community above and beyond serving one’s own Center. Core A will lead this NIDDK shared vision.

Funding Agency:

NIDDK

Principal Investigator:

Dr. William Ricke

Project Summary:

No consequential advances in medical treatment of prostate-related lower urinary tract symptoms (LUTS) have emerged in decades. Existing medical therapies improve LUTS but robustness of these effects are marginal. Not all men respond to existing therapies, some respond with adverse effects requiring discontinuation of therapy, and most experience a progressive worsening of symptoms pursuant to initial relief. Multiple mechanisms drive development and progression of prostate-related LUTS. The overarching goal of the O’Brien Center for Benign Urology Research is to identify mechanisms that result in lower urinary tract dysfunction and prostate-related LUTS. The overarching hypothesis of the center is that fibrosis is a cause of male LUTS. In contrast to benign prostatic enlargement and smooth muscle dysfunction, prostatic fibrosis remains untargeted by existing therapies. In order to advance the scientific understanding and medical management of prostatic fibrosis, it will be necessary to: (1) identify cellular and molecular mediators of fibrosis and therapeutically- susceptible pathways using clinical specimens, (2) develop and validate preclinical mouse models of prostatic fibrosis and strategies for granular assessment of voiding function, (3) test new therapies in these preclinical models with the long term goal of treating fibrosis in men, and (4) develop new non-invasive radiologic imaging strategies with the long-term goal of diagnosing prostatic fibrosis in men. Two additional goals will advance the urologic research community: (1) develop and publicly disseminate resources to increase research efficiency, reproducibility, and rigor, and (2) cultivate an outstanding educational enrichment program to attract and retain young basic- and physician-scientists into the benign urologic research field. The Center will apply state of the art molecular and histological methods to visualize and characterize fibrosis in a range of human and animal prostatic tissues and examine how prostatic fibrosis develops, progresses, and responds to treatment. Interactions and engagement with the O’Brien Centers’ Interaction Core, the UW O’Brien Centers Website, and GUDMAP will accelerate the dissemination of data, software, methods, and tissue resources to the greater biomedical community. The leadership and experience within the Center will allow for the promotion of interactions among Center Projects, the Biomedical Research Core, and other Centers (U54, P20, K12) through communication, collaboration, and coordination. The larger vision is that O’Brien Centers will be a nidus for ideas, research, resources, training, and a unified voice across the urologic research community. To realize this vision, the Centers must become more than the sum of their parts. The UW O’Brien Center and its affiliates will contribute to this synergism by leveraging existing Center assets and relationships, conducting rigorous investigation, fostering teaching and learning, and through vigorous pursuit of innovation. With the solid financial support and “buy-in” from UW and its affiliates, Core A will lead this vision for this O’Brien Center.

Funding Agency:

NIH/NIEHS

Principal Investigator:

Dr. Richard Peterson

Project Summary:

Clinical management of urinary disorders costs Americans over four billion dollars annually, demanding a better understanding of risk factors that underlie or contribute to these disorders. We provide compelling evidence for a new paradigm that a man’s fetal and neonatal environment determines his risk of developing urinary complications of benign prostatic disease in adulthood.

The proposed studies offer needed insight into disease pathogenesis, incidence, and why some men develop urinary complications of benign prostate hyperplasia (BPH) at a younger age or with more severe symptoms than others. Our preliminary results show in utero and lactational (IUL) exposure to 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) causes severe urinary dysfunction in mice susceptible to BPH. TCDD is a widespread contaminant, ubiquitous in serum of American men, and a selective activator of the aryl hydrocarbon receptor (AHR), a receptor that can be activated by many persistent organic pollutants. We isolated two potential mechanisms by which IUL TCDD exposure impairs urinary function: by increasing sensory nerve fibers during lower urinary tract development and by enhancing estrogen receptor signaling. We also discovered that age of mice at the time of TCDD exposure determines the impact on mouse urinary function. Adult TCDD exposure has the opposite effect of IUL exposure – it protects against urinary dysfunction in mice susceptible to urinary complications of BPH.

These findings create a remarkable opportunity to test whether AHR activation in the prostate and lower urinary tract of adult males is therapeutic for urinary dysfunction. We synthesized novel selective AHR modulators (SAHRMs), verified their potency in vitro, and will perform pre-clinical testing in vivo. This proposal’s three specific aims will test the following hypotheses: (1) IUL TCDD exposure increases the number of sensory nerve fibers in the prostate and prostatic urethra, having a lasting effect on urinary function, (2) IUL TCDD exposure impairs urinary function through a mechanism requiring stromal estrogen receptor-alpha (ERα), and (3) the impact of TCDD exposure on urinary function differs depending on when exposure occurs, perinatal period versus adulthood. As part of aim 3, we will also test the hypothesis that adult exposure to SAHRMs, which lack TCDD-like toxicity, offers therapeutic benefit by reducing urinary dysfunction in BPH susceptible mice. By establishing a mechanistic connection between TCDD exposure and urinary function, the proposed studies launch original lines of research into a disease process never before linked to developmental origins or AHR signaling. We also expect to reveal the AHR as a new therapeutic target for treating urinary complications of BPH, a disease against which current drugs are only marginally effective.