1997 — 2001 |
Hayward, Simon W. |
R29Activity Code Description: Undocumented code - click on the grant title for more information. |
Biological Activity of Igf and Fgf in the Human Prostate
DESCRIPTION The long-term objective of this research project is to develop a better understanding of the cell-cell signaling mechanisms involved in the development, maintenance and disease of the human prostate. The main goal of this application is to investigate the ontogeny and androgen regulation of insulin-like growth factors -1 (IGF-I) and -II, fibroblast growth factors -2 (FGF-2) and -7 and their receptors in the growing fetal and the growth-quiescent adult human prostate in vivo. Expression of these molecules in benign prostatic hyperplasia and prostate cancer will be assessed to determine whether IGF-I and -II and FGF-2 and -7 are involved in prostatic disease. The hypothesis of this project is that expression of specific growth factors is determined by a combination of androgen action and the differentiation state of the epithelial and stromal compartments of the prostate tissue. Androgens induce the expression of autocrine and paracrine acting growth factors which mediate specific developmental events in the prostate. Additionally, the pattern of growth factor expression varies, not only with developmental status but also with tissue pathology, to control local proliferation or growth quiescence. This hypothesis will be tested through the following specific aims: 1) analysis of the expression of FGF-2 and -7 and IGF-I and -II and their receptors by epithelium and mesenchyme during human prostatic growth and differentiation; 2) analysis of the expression of FGF-2 and -7 and IGF-I and -II and their receptors by epithelium and stroma in the growth quiescent human prostate; 3) analysis of the expression of FGF-2 and -7 and IGF-I and -II and their receptors in the epithelium and stroma of the human prostate following castration and subsequent androgenic stimulation; 4) the role of FGF-2 and -7 and IGF-I and-II in controlling prostatic mitogenesis and morphogenesis in vitro; and 5) analysis of the expression of FGF-2 and -7 and IGF-I and -II and their receptors in human prostatic disease. The models to pursue these aims will be subrenal capsule grafts of fetal and adult human prostate tissue and heterospecific tissue recombinants composed of rat urogenital sinus mesenchyme recombined with human prostate epithelium. We will also use explant culture and tissue from samples of benign prostatic hyperplasia and prostate cancer. Qualitative and quantitative analysis will be by RTPCR, species specific RT-PCR, RNase protection, Northern and Western blotting. Proteins will be localized by immunocytochemistry. The biological effects of the growth factors will be examined in vitro, using application of exogenous growth factors and blockade of their production and action.
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1 |
2001 — 2005 |
Hayward, Simon W. |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Hormonal Carcinogenesis in Rb-Knockout Mouse Prostate
The overall objective of this work is to enhance the understanding of prostate cancer initiation and progression. The main goal of the present proposal is to characterize new models of hormonal carcinogenesis in the mouse prostate. These experiments will use retinoblastoma (Rb) gene-knockout and conditionally deleted-Rb mouse prostate as a target for hormonal carcinogenesis. Experiments will examine the ontogeny and histopathology of carcinogenesis (aim 1), the precise role played by sex steroids (aim 2) and the specific epithelial cell type targeted by hormonal carcinogens (aim 3). A panel of cell strains will be derived from the tumors which are generated. Their behavior in vivo will be characterized and they will be subject to genomic analysis to identify common genetic lesions associated with prostate cancer (aim 4). Data from these studies will be used to identify candidate genes involved in prostatic carcinogenesis. The central hypothesis is that the progression from normal histology to cancer seen in mouse prostatic tissue lacking expression of the Rb tumor-suppressor gene is a good in vivo model of human prostate cancer. This project will use two new in vivo models of prostatic carcinogenesis. The first is a tissue recombination model based upon prostatic epithelium derived from the Rb-knockout mouse. The second model is a conditional deletion of Rb in the luminal epithelial cells of the prostate utilizing cre-lox technology. In both models a combination of testosterone and estradiol will be used to initiate the formation of prostate tumors. Prostate tumors will be used to generate a spectrum of cell lines representative of the stages from normal prostate to hormone- independent prostate cancer. These cell lines will serve as a source material to examine genomic lesions associated with prostate cancer progression. The following specific aims will be pursued. Specific Aim 1 Characterization of tumor progression in Rb-deficient mouse prostate under the influence of testosterone and estradiol. Specific Aim 2 An examination of the roles of testosterone and estradiol in hormonally induced prostatic carcinogenesis in the Rb-deficient mouse prostate Specific Aim 3 Generation and Characterization of ARR2Pb-cre RbloxP/loxP mice. Hormonal Carcinogenesis in ARR2Pb-cre RbloxP/loxP mice. Specific Aim 4 Isolation, phenotypic and genomic characterization of Rb-deficient cell strains.
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1 |
2003 — 2004 |
Hayward, Simon W. |
U01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Genetic Markers of Transition Zone Hyperplasia
DESCRIPTION (provided by applicant): BPH is characterized pathologically by glandular and stromal hyperplasia leading to nodular expansion of the transition zone (TZ). As many as 50 % of males will require some form of treatment in their lifetime. Screening tests to assess risk for developing symptomatic BPH and tissue or blood based tests to stratify disease severity and to predict treatment response do not exist. BPH is extremely common in the TZ of radical prostatectomies performed for prostate carcinoma. Therefore to screen for candidate biomarkers we will utilize a large bank of snap frozen TZ tissues (> 2000 from > than 500 patients, including MTOPS trial patients) procured intraoperatively during RPs over the last several years. Three parallel screening strategies will be adopted: 1) cDNA microarrays will be used to detect genes that have altered expression correlating with disease severity; 2) TZ tissues implanted in the renal capsule of SCID mice will be used to identify genes regulated by androgens and the nuclear receptor peroxisome proliferator activated receptor gamma (PPAR() in human prostate in vivo by comparing gene expression in tissues from intact or castrated mice with or without treatment with agents such as testosterone, finasteride and ligands for PPARgamma; 3) data base mining will be used to identify candidate genes which can then be studied for altered expression in progressively severe BPH and for allelic variation in blood drawn from BPH patients. The combination of these strategies will allow identification of genes, or groups of genes by more than one approach. Correlation of expression of these genes in samples with progressively severe BPH will be confirmed by real time RT-PCR and epithelial and/or stromal localization of candidate genes will be determined by immunohistochemistry and in situ hybridization. Hormonally modulated genes and those that are involved in regulating epithelial-stromal interactions are likely to be useful markers for disease and/or targets for novel therapeutics. Analysis of the results from these different strategies will indicate candidate genes to investigate for their role in regulating epithelial-stromal interactions in a tissue recombination system allowing for selectively manipulating gene expression in either prostate epithelium or stroma. This integrated interdisciplinary approach involving prostate investigators in Pathology, Urology, and Medical Genetics and key Core facilities at Vanderbilt will facilitate the success for this program. Large volumes of available cases and novel detection strategies will allow for the discovery and characterization of biomarkers useful in managing BPH patients. Models employed will be useful for characterizing the role of novel gene targets identified within the MTOPS Consortium as well as for testing new therapeutic strategies.
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1 |
2004 — 2013 |
Hayward, Simon W. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Paracrine Regulation of Bph Pathogenesis
DESCRIPTION (provided by applicant): The long-term objective of the work proposed in this project is to provide a firm groundwork of biological information allowing an understanding of the processes involved in the normal and pathological growth of the human prostate in vivo. The central hypothesis of this application is that paracrine interactions between the epithelial and stromal compartments of the prostate are responsible for BPH pathogenesis. The transforming growth factor-betas (TGFbeta) and their receptors (TGFbeta-R) are implicated in the regulation of proliferation and apoptosis in the prostatic epithelium. TGFbeta is also thought to be involved in the differentiation of a smooth muscle phenotype in the prostatic stroma. We will examine the expression and role of TGFbeta ligands, receptors and downstream activation of the TGFbeta signaling pathway in human prostatic tissue. We will then examine the effects of selectively either deleting expression or controllably over expressing these proteins in human prostatic tissue in vivo to determine their effects on epithelial and stromal differentiation and thus determine their ability to regulate prostatic pathology. The focus of this work is to demonstrate the mechanistic role, which TGFbeta signaling plays in maintaining adult homeostasis by regulating paracrine interactions between epithelial and stromal cells, and how inappropriate changes in such signaling might mimic BPH. The following specific aims will be pursued: Specific Aim 1: Expression and sex steroid hormone regulation of TGFbeta signaling molecules in developing, normal adult and hyperplastic adult human prostatic tissue. Specific Aim 2: Effects on downstream signaling pathways of controlled overexpression of TGFbeta signaling in growing, growth-quiescent, and regressing human prostatic tissue in vivo. Specific Aim 3: Controlled deletion of TGFbeta signaling in growing, growth-quiescent, and regressing human prostatic tissue in vivo, mechanistic effects.
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1 |
2006 — 2010 |
Hayward, Simon W. |
U54Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These differ from program project in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes, with funding component staff helping to identify appropriate priority needs. |
Paracrine Tgf-Beta Signaling in Prostate Cancer Initiation and Progression |
1 |
2007 |
Hayward, Simon W. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Paracrine Regulation of Benign Prostate Hyperplasia Pathogenesis
DESCRIPTION (provided by applicant): The long-term objective of the work proposed in this project is to provide a firm groundwork of biological information allowing an understanding of the processes involved in the normal and pathological growth of the human prostate in vivo. The central hypothesis of this application is that paracrine interactions between the epithelial and stromal compartments of the prostate are responsible for BPH pathogenesis. The transforming growth factor-betas (TGFbeta) and their receptors (TGFbeta-R) are implicated in the regulation of proliferation and apoptosis in the prostatic epithelium. TGFbeta is also thought to be involved in the differentiation of a smooth muscle phenotype in the prostatic stroma. We will examine the expression and role of TGFbeta ligands, receptors and downstream activation of the TGFbeta signaling pathway in human prostatic tissue. We will then examine the effects of selectively either deleting expression or controllably over expressing these proteins in human prostatic tissue in vivo to determine their effects on epithelial and stromal differentiation and thus determine their ability to regulate prostatic pathology. The focus of this work is to demonstrate the mechanistic role, which TGFbeta signaling plays in maintaining adult homeostasis by regulating paracrine interactions between epithelial and stromal cells, and how inappropriate changes in such signaling might mimic BPH. The following specific aims will be pursued: Specific Aim 1: Expression and sex steroid hormone regulation of TGFbeta signaling molecules in developing, normal adult and hyperplastic adult human prostatic tissue. Specific Aim 2: Effects on downstream signaling pathways of controlled overexpression of TGFbeta signaling in growing, growth-quiescent, and regressing human prostatic tissue in vivo. Specific Aim 3: Controlled deletion of TGFbeta signaling in growing, growth-quiescent, and regressing human prostatic tissue in vivo, mechanistic effects.
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1 |
2007 |
Hayward, Simon W. |
R13Activity Code Description: To support recipient sponsored and directed international, national or regional meetings, conferences and workshops. |
16th Annual Meeting of the Sbur: Stromal-Epithelial Interactions in Urology
[unreadable] DESCRIPTION (provided by applicant): [unreadable] This proposal seeks funds to provide 30 travel awards of $750 each to trainee investigators (graduate [unreadable] students, residents, clinical and postdoctoral fellows and faculty below the rank of Assistant Professor) to participate in the Fall 2006 meeting of the Society for Basic Urologic Research (SBUR) which will be held in Phoenix, AZ on November 16-19th. The SBUR is a society of scientists specializing in research on benign and malignant urologic diseases as the basic biology of prostate, kidney and bladder. The membership also has broader interests in other areas including autoimmune urologic diseases, infectious diseases, neuro-urologic diseases, male reproductive biology, infertility and erectile dysfunction. This 2006 meeting turns to the idea of stromal-epithelial interactions in urology. Microenvironmental influences are accepted as key players in carcinogenesis in addition to their more traditionally defined roles in development. We will explore the role of stromal-epithelial interactions in developmental, benign and malignant diseases of the urogenital tract. The trainee attendees will be provided with opportunities to network among their peers and with more senior and established members of the Society and to present their data at poster sessions and in selected cases as [unreadable] podium presentations. The invited speakers are, without exception, the leaders in their respective field with extensive knowledge and experience to offer. The SBUR annual meetings have always been representative of the highest level of research accomplishments in the topic areas and themes chosen for each meeting. The atmosphere of the Society and its meetings are personable and informal, providing encouragement and unique opportunities for students and post-doctoral fellows to participate and establish collaborations. In order for such interactions to occur, these trainee investigators need support for their travel expenses and hotel costs. If funded this proposal will contribute significantly to the support available and will thus contribute significantly to the success of the educational objectives of this meeting. [unreadable] [unreadable] [unreadable]
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1 |
2009 |
Hayward, Simon W. |
R56Activity Code Description: To provide limited interim research support based on the merit of a pending R01 application while applicant gathers additional data to revise a new or competing renewal application. This grant will underwrite highly meritorious applications that if given the opportunity to revise their application could meet IC recommended standards and would be missed opportunities if not funded. Interim funded ends when the applicant succeeds in obtaining an R01 or other competing award built on the R56 grant. These awards are not renewable. |
Paracrine Regulation of Bph Pathogeneis
PROJECT SUMMARY: Benign prostatic hyperplasia (BPH) is an important cause of morbidity in the adult male population and is the most common symptomatic tumor-like condition in humans. Clinically BPH results in urethral constriction with a consequent slowing of urinary flow rates and an inability to properly empty the urinary bladder. In the western world, BPH is not a life threatening condition. However, it is a condition with significant associated morbidity and consequent healthcare costs. BPH results in a variety of problems including nocturia, frequency, urgency and post-mictural dribbling and, more seriously it can cause renal insufficiency (with rising serum creatinine), frequent urinary tract infections and urosepsis due to insufficient urinary draining. For many decades the core of research into BPH has centered around androgen and estrogen signaling. These studies have given rise to the development of 5[unreadable]-reductase inhibitors such as finasteride and dutasteride. However, these directions have not shown much recent progress in developing new approaches to improve the condition of patients. New concepts are sorely needed to move the field forward. The central hypothesis of this proposal is that prostatic inflammation results in a profile of stromal changes which contribute to focal benign glandular expansion. The long term goal of this work is to identify pathways which can be co-targeted ether alone as a form of chemoprevention or along with current standard BPH therapies to provide safe and long term symptomatic relief. This proposal addresses a number of the high priority recommendations of the recently published NIDDK Prostate Research Strategic Plan including;the creation of new models;the development of an understanding of the signaling, interaction and crosstalk between multiple cell types in the prostate;and the characterization of disease-relevant cellular pathways for potential therapeutic applications. The three specific aims in this proposal address interlocking aspects of BPH pathogenesis. The first aim looks at the effects of inflammatory cytokine expression on prostatic epithelial and stromal differentiation. The second aim examines the consequences of these changes in relation to the recruitment of bone marrow-derived cell populations and the contribution that these play in hyperplastic growth. The third aim examines the application of anti-inflammatory approaches to test the effects of such strategies on BPH pathogenesis.
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1 |
2010 — 2011 |
Hayward, Simon W. |
P20Activity Code Description: To support planning for new programs, expansion or modification of existing resources, and feasibility studies to explore various approaches to the development of interdisciplinary programs that offer potential solutions to problems of special significance to the mission of the NIH. These exploratory studies may lead to specialized or comprehensive centers. |
Ppar-Gamma and Bph/Luts
DESCRIPTION (provided by applicant): The RFA, to which this Planning Center proposal is a response, is designed to encourage the establishment of a critical mass of investigators from a variety of backgrounds, to educate and inform the research community about the problems associated with benign urologic disease, and to develop components of the preliminary data and infrastructure which will be needed for subsequent Research Center proposals. It is clear that the problem of BPH/LUTS cannot be studied without a broader understanding of the relationship of this syndrome with other associated co-morbidities. The existence of many interacting and interrelated centers at Vanderbilt (Figure 1) makes this an ideal site to establish a Center in this area and for this reason we believe that such a Center is a goal which can be productive and should be pursued. Therefore the Planning Center to be established in this P20 proposal has the following goals: Help to create an environment that supports important and innovative research. Raise awareness and interest in BPH/LUTS and its relationship to other significant co-morbidities. Enhance benign urologic research education for students, scientists, and clinicians. Foster interdisciplinary collaborations, especially in the emerging areas of research, to catalyze new ideas and scientific approaches.
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1 |
2012 — 2013 |
Hayward, Simon W. |
P20Activity Code Description: To support planning for new programs, expansion or modification of existing resources, and feasibility studies to explore various approaches to the development of interdisciplinary programs that offer potential solutions to problems of special significance to the mission of the NIH. These exploratory studies may lead to specialized or comprehensive centers. |
Obesity, Inflammation and Bph
DESCRIPTION (provided by applicant): Our overall approach is brings together a multidisciplinary team to determine the role of obesity in the development of benign prostatic hyperplasia (BPH). The research team has expertise in biological modeling of urogenital tract disease, epidemiology, and medicine, with special emphasis on model development and clinical manifestations of obesity, inflammation, and metabolic stress. The overall hypothesis is that benign hyperplastic growth of the prostate and associated inflammatory responses are influenced by obesity and diet. We further hypothesize that some of these changes may be reversed by appropriate dietary or surgical interventions, while others may become fixed. The project is broken into three aims, all centered on the links between BPH, inflammation, and obesity. The first aim will test prostatic histopathologic changes, immune/inflammatory cell recruitment and systemic inflammatory marker changes induced in wild type, leptin receptor knockout (ob/ob) and low density lipoprotein receptor knockout (LDLR-/-) C57/BL6 mice by high fat/high sucrose or high fat/high corn starch dietary regimens. Our preliminary data demonstrate that these models undergo prostatic changes consistent with aspects of human BPH. The second aim will examine the reversibility of these phenotypic and inflammatory changes using caloric restriction and Roux-en-Y gastric bypass (RYGB) surgery. These techniques will be applied to the mouse models at specific times in the development of inflammation and hyperplasia to determine which aspects of the disease process can be reversed by altering dietary habits. The third aim will take advantage of a NIDDK supported, prospective epidemiologic study of men with BPH (the Nashville Men's Health Study) to determine if blood and urine biomarkers of obesity and inflammation and insulin expression and sensitivity are associated with levels of prostate tissue inflammation or BPH symptom progression over time. Specific Aims one and two are designed to determine the role of obesity in the induction and maintenance of specific markers of prostatic hyperplasia. Aim three extends these concepts to obesity, prostate tissue inflammation, and BPH progression in humans. The integration of these aims across mouse models and human epidemiology with overlapping biomarker panels will ground the mouse models to the clinical realities of human BPH, while also developing an understanding of the mechanisms underlying disease pathogenesis.
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1 |
2014 — 2017 |
Hayward, Simon W. |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Ap-1 Factors in the Pathogenesis and Progression of Benign Prostatic Hyperplasia @ Northshore University Healthsystem
DESCRIPTION (provided by applicant): Benign prostatic hyperplasia (BPH) and associated Lower Urinary Tract Symptoms (LUTS) are a major public health problem with high morbidity and associated costs. At present, BPH patients are treated fairly uniformly. However, a true understanding of the disease process and the role of comorbidities in driving progression should allow stratification of patients into sub-groups and a more personalized approach to therapy, leading to better efficacy and lower rates of surgical intervention. We have recently developed a human BPH tissue repository composed of samples of incidental BPH found at prostatectomy and of tissue from patients whose BPH had progressed to surgical intervention. We also investigated how mouse models of diabetes and obesity reflect specific aspects of human BPH. This provides new tools to address questions relating to specific components of human BPH and to correlate murine responses to human samples. Two key observations have emerged in our recent studies. First, gene expression changes in the progression from incidental BPH to symptomatically severe, medically-refractory disease showed a pattern that mirrored changes seen in a number of chronic inflammatory conditions such as psoriasis, arthritis and inflammatory bowel disease. These changes prominently included basal cell expression of AP-1 factors, notably c-FOS, which were associated with disease progression to surgery and also with resistance to 5ARI therapy. Second, we determined that obese (Ob/Ob) and non-obese diabetic (NOD) mice show distinct features of prostatic enlargement and inflammation that mirror aspects of human BPH. The purpose of the proposed work is to define the role of AP-1 stress responses in prostatic hyperplasia and to determine whether drug regimens that affect such pathways alter the progression of prostatic hyperplasia. To address these ideas three Specific Aims are proposed. Specific Aim 1. Determine whether specific systemic stressors affect AP-1 signaling and prostate histopathology. This aim tests the hypothesis that diabetes, obesity and inflammation will give rise to distinct patterns of AP-1 factor activation and associated growth in the mouse prostate and that these changes will be reflected in human samples. Specific Aim 2. Determine whether tissue-specific AP-1 factors drive inflammation, prostatic hyperplasia and resistance to therapy. This aim tests the hypothesis that prostatic hyperplasia can be rendered resistant to androgen ablation by AP-1 factor activation secondary to diabetes, obesity or inflammation. Specific Aim 3. Determine whether reversing obesity, diabetes or inflammation reduces prostatic hyperplasia. This aim tests the hypothesis that reducing AP-1 activity by reversing obesity, diabetes or inflammation will reduce hyperplasia and restore sensitivity to therapy.
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1 |
2015 |
Fowke, Jay H Hayward, Simon W. |
U54Activity Code Description: To support any part of the full range of research and development from very basic to clinical; may involve ancillary supportive activities such as protracted patient care necessary to the primary research or R&D effort. The spectrum of activities comprises a multidisciplinary attack on a specific disease entity or biomedical problem area. These differ from program project in that they are usually developed in response to an announcement of the programmatic needs of an Institute or Division and subsequently receive continuous attention from its staff. Centers may also serve as regional or national resources for special research purposes, with funding component staff helping to identify appropriate priority needs. |
Mechanisms of Bph Progression @ Northshore University Healthsystem
?DESCRIPTION (provided by applicant): Chronic inflammation is a well-established feature of BPH. In this Center proposal, we show that activation of the NF-?B pathway, a response to inflammation is associated with increased prostatic volume and therapeutic failure in symptomatic BPH. We also show that NF-?B activation leads to the expression of an AR variant isoform, AR-V7, which lacks a ligand binding domain of the AR. Furthermore, we show that BPH patients who no longer respond to treatment have greater NF-?B activation and AR-V7 expression in the prostate transition zone compared to incidental BPH patients, consistent with a loss of sensitivity to 5?-reductase inhibitors (5ARI). Similarly, 5ARI therapy appears less effective among obese patients consistent with chronic systemic inflammation, and NF-?B activation. The goal of this Center is to determine the pathways linking obesity, inflammation, NF-?B activity, and AR-V induction driving BPH progression and drug therapy failure. We propose three interlinked projects to determine the consequences of inflammation and NF-?B activation. The first project utilizes tissue and data from the Medical Therapy of Prostatic Symptoms (MTOPS) clinical trial to identify changes in NF-?B, IL-6, and AR-V activity over time in the prostate transition zone and the association with BPH progression and response to therapy. The second project uses our human BPH tissue repository for an expansive investigation of the links between inflammatory macrophages and disease progression, then utilizes xenograft models to interrogate the specific roles of NF-?B, AR-V and obesity in BPH resistance to 5ARI therapy. The third project is a detailed investigation of the molecular mechanisms underlying the interactions between AR function, AR-V expression and the activity of NF-?B and 5?-reductase in human prostatic cells. The Center's Tissue and Data Biorepository and Administrative Cores play critical roles in these investigations, including tissu acquisition, histopathologic assessment, data management, and biostatistical and bioinformatic analysis. Importantly, we will bring novel resources and expertise to the NIDDK program, including extensive RNA-seq data from the MTOPS trial samples and a large and growing human BPH tissue repository with linked patient data to enable the future exploration of novel hypotheses as they develop. The Center will also support an Educational Enrichment program that will provide instruction and connections to the research community and training opportunities to students at the undergraduate and medical school levels.
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0.948 |
2018 — 2021 |
Hayward, Simon W. Thumbikat, Praveen (co-PI) [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Inflammatory Pathways in Bph/Luts @ Northshore University Healthsystem
PROJECT SUMMARY/ABSTRACT Lower urinary tract symptoms (LUTS) due to benign prostatic hyperplasia (BPH) is a common, complex and poorly understood condition. Inflammation is strongly associated with increased LUTS severity and also with the failure of medical treatment for BPH, resulting in progression to surgery. Despite this complexity, clinical BPH treatment normally follows a scripted format using two medical approaches: ?-adrenergic blockers (?- blockers) to relax muscle tone and 5?-reductase inhibitors (5ARI) to shrink the prostate. Many men fail these medical treatments, resulting in around 120,000 surgical interventions annually in the U.S. We have shown that advanced human BPH has a profile of gene expression reminiscent of changes seen in autoimmune inflammatory (AI) conditions such as rheumatoid arthritis (RA) and psoriasis. Data from a review of over 120,000 patient records demonstrated that BPH is positively correlated with the diagnosis of AI conditions, and that treatment of AI conditions, specifically with TNF? antagonists, reduces subsequent BPH diagnoses. This positively links BPH to other inflammatory conditions and shows that specific drug regimens used to treat these diseases indicate avenues for BPH therapy. Loss of Th1/Th2 and Th17/Treg balance has been reported in several inflammatory autoimmune diseases and may be responsible for the development and progression of RA. Th1 and Th17 cells are implicated in many inflammatory conditions in humans and mice, while an opposing anti-inflammatory role is attributed to Th2 and Treg cells. Likewise, our preliminary data show that the M1/M2 macrophage balance changes to a more inflammatory phenotype as BPH progresses. M1 macrophages, in turn, drive Th1/Th17 polarization to maintain a proinflammatory state in the prostate. Mast cells play a role in BPH and are also recognized mediators of the increase in inflammation seen in diseases such as RA. We hypothesize that changes in the immune/inflammatory environment are major drivers of BPH pathogenesis. The proposed work centers around this idea. We will define the immune/inflammatory environment during human BPH progression to quantify changes relative to increases in Th1/Th2, Th17/Treg and M1/M2 macrophage ratios as the disease progresses. We will then utilize a series of murine models to test the consequences of manipulating the immune/inflammatory environment in relation to the cell types present, as well as the intercellular signaling environment to test the premise that specific inflammatory cell or associated chemokines can regulate prostate growth. The final aim will examine the role of current medical approaches aimed at specific cytokine signaling pathways and determine whether these are effective at reducing prostatic hyperplasia in a model of prostatic inflammation.
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0.948 |
2019 |
Hayward, Simon W. |
P20Activity Code Description: To support planning for new programs, expansion or modification of existing resources, and feasibility studies to explore various approaches to the development of interdisciplinary programs that offer potential solutions to problems of special significance to the mission of the NIH. These exploratory studies may lead to specialized or comprehensive centers. |
Leukocytic Phenotypes Associated With Bph Progression @ Northshore University Healthsystem
OVERALL: SUMMARY The goals of this Center for Benign Urological Diseases are: 1) to create and maintain an environment that supports important and innovative research in the field of benign urology by focusing on a Scientific Research Project examining ?Leukocyte phenotypes associated with BPH progression,? 2) to educate and inform young scientists and physicians about BPH, and 3) to develop new interactive projects and collaborations involving other groups in the benign urology research community. The program brings together expertise in basic science, bioinformatics, and clinical urology to apply new technologies in the field of benign urologic research. The research team includes members from the benign and malignant urology fields as well as from non- urologic cancers. Benign prostatic hyperplasia (BPH) and associated lower urinary tract symptoms (LUTS) are highly prevalent and will become increasingly more frequent with an aging demographic. Approximately one- third of BPH patients are resistant to current medical therapy, and a further third of initial responders (around 10% of the total patient population) subsequently develop therapy resistance after an initial positive response. So, for around 40% of the patient population there is no effective medical therapy, leaving surgery as the sole treatment option. Approximately 120,000 surgeries are performed annually in the United States to treat men who are resistant to the available medical interventions. Many of these are elderly patients often with significant co-morbidities who are often not ideal surgical candidates. BPH is closely associated with pro- inflammatory co-morbidities. However, the characteristics and pathways linking immune/inflammatory changes to BPH progression are unclear. We show in preliminary data that TNF? antagonists can reduce the incidence of BPH in patients with autoimmune inflammatory conditions suggesting that a more complete understanding of the leukocyte signaling network in the prostate could elucidate new therapeutic targets. This proposal will utilize single-cell (sc)RNA-seq to fully characterize the leukocyte population in patients with small prostates and low IPSS scores vs. those with large prostates, high symptom scores, and progression to surgery specifically for a BPH indication. This will provide a comprehensive picture of the cells that are present and will allow for the application of bioinformatics approaches to define the extracellular signaling pathways that are activated in these inflammatory cells as disease progresses. The Administrative Core coordinates all Center activities, maintains financial and administrative oversight, manages the Educational Enrichment Program charged with the education of the next generation of scientists, and informs scientists and clinicians of our work. The Administrative Core also coordinates with the NIDDK and the other IR-BU Centers and integrates our approaches with the wider benign urologic research community.
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0.948 |
2019 |
Hayward, Simon W. |
P20Activity Code Description: To support planning for new programs, expansion or modification of existing resources, and feasibility studies to explore various approaches to the development of interdisciplinary programs that offer potential solutions to problems of special significance to the mission of the NIH. These exploratory studies may lead to specialized or comprehensive centers. |
Administrative Core @ Northshore University Healthsystem
ADMINISTRATIVE CORE: SUMMARY The Administrative Core of this Center for Benign Urologic Diseases serves as a focus for synergy in the Center and performs a number of roles essential to its smooth running. In particular; the Administrative Core provides financial oversight and management, formalizes interactions between researchers at the two institutions, and facilitates communication. It ensures open interactions with other entities at both local and institutional levels, and coordinates the Educational Enrichment Program. The Core advertises the work of the center and hosts a website to publicize these efforts. In addition, the Core will organize and manage regular research meetings involving all personnel involved in the Center. The annual scientific meetings are also planned and supported by this Core. The goals of the Administrative Core are to provide central organization and oversight of the Scientific Research Project, coordinating the efforts with the broader research community as well as institutionally, locally, and nationally through the NIDDK and the Cooperative Research Centers Program. This Core also communicates the work of the Center through training and dissemination of results within the Educational Enrichment Program. The aims of the Core are: 1. Administrative Support for all financial and reporting aspects of the Center, 2. Organization and execution of Research Meetings, 3. Integration of this project with the greater Research Community, and 4. Management of the Educational Enrichment Program through training and scientific meetings.
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0.948 |