Mechanisms of Fatty Acid Metabolism in Prostate Differentiation and Disease

脂肪酸代谢在前列腺分化和疾病中的机制

基本信息

批准号：
9352679
负责人：
Douglas William Strand
金额：
$ 13.75万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-17 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9352679
关键词：
Ablation Academic Medical Centers Advisory Committees Affect Aging Androgen Receptor Basal Cell Benign Benign Prostatic Hypertrophy Biochemical Markers Biomedical Research Biometry Body mass index Carbohydrates Cell Communication Cells Chromosome Mapping Chronic Clinical Clinical Management Data Development Diabetes Mellitus Diabetic mouse Diffusion Disease Down-Regulation Enrollment Environment Epidemiologist Epidemiology Epithelial Epithelial-Stromal Communication Epithelium Experimental Models Fatty Acids Fostering Functional disorder Funding Opportunities Gene Targeting Genes Genetic Markers Genitourinary system Goals Grant Growth Healthcare Systems High Fat Diet Homeostasis Human Hyperplasia Hypertrophy Implant In Vitro Inbred NOD Mice Incidence Inflammation Inflammatory Institutes Institution Instruction Insulin Insulin Resistance Intervention Interview Knockout Mice Laboratories Lead Leptin Link Manuscripts Mediating Mediator of activation protein Medical Mentors Metabolic Metabolic Diseases Metabolic stress Metabolism Modeling Molecular Morbidity - disease rate Mus National Institute of Diabetes and Digestive and Kidney Diseases Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity Occupations Operative Surgical Procedures Oxidoreductase PPAR gamma Patients Pharmaceutical Preparations Preparation Prostate Prostatic Prostatic hypertrophy Proteomics Pump Research Research Personnel Research Training Resistance Stanolone Testing Therapeutic Tissues Training Training Activity Training Programs Transgenes United States National Institutes of Health Urology base career development diabetic diabetic patient fatty acid metabolism fatty acid oxidation flexibility glucose uptake immunoregulation improved in vivo insight insulin sensitivity lower urinary tract symptoms meetings men mouse model novel outreach program paracrine prevent programs public health relevance pyruvate dehydrogenase kinase 4 resistance mechanism therapeutic target therapy resistant three-dimensional modeling traditional therapy uptake

项目摘要

DESCRIPTION (provided by applicant): The overall goal of this proposal is to develop my technical and professional abilities to become an independent investigator at a top-tier academic institution capable of providing a fully supportive research environment for my pursuit of the molecular links between systemic metabolic stress and chronic urogenital dysfunction. This will be pursued through a scientific project that will determine how systemic metabolic alterations affect local prostatic metabolism and differentiation. I will continue to foster strong interdisciplinary relationships with epidemiologists, diabetologists and molecular biologists to capitalize on the novel models of stromal-epithelial interactions developed in our laboratory. To achieve these goals, I will enroll in research training activities provided by the NIH/MMPC/NIDDK, the Vanderbilt University Medical Center Biomedical Research and Training office and the Vanderbilt Institute for Clinical Training and Research. These include meetings on mouse and experimental models for metabolic research, biostatistics and proteomics analysis. The Vanderbilt Diabetes and Research Training Center also provides funding opportunities, meetings and seminars in conjunction with its Enrichment, Training and Outreach Program. Additional career development mechanisms will include instructive seminars at national meetings on obesity, diabetes and urology, mentored guidance in grant and manuscript preparation, and academic job interviewing. An advisory committee will evaluate the completion of both my scientific and career development milestones and facilitate my transition to an independent investigator. Benign prostatic hyperplasia and associated lower urinary tract symptoms (BPH/LUTS) are a severe physical and financial burden, which, given their association with aging and metabolic dysfunction, will continue to increase in terms of the number afflicted. Moreover, clinical management of BPH/LUTS has reached limitations in efficacy, predominantly due to a poor understanding of the mechanisms of therapeutic resistance in obese and diabetic patients. Increased focus on the fundamental metabolic mechanisms governing prostatic differentiation and immunomodulation is needed to identify new targets for preventing benign growth and inflammation in obese and diabetic patients. Based on our preliminary studies in mice and humans, I hypothesize that insulin-regulated carbohydrate/fatty acid flux is a key mediator of the differentiation program driven by tissue interactions in prostate and that obesity and type II diabetes disrupt this homeostasis leading to hypertrophy and inflammation. The specific aims of this study are as follows: Aim 1: Determine whether basal cell fatty acid oxidation inhibits luminal epithelial differentiation. Aim 2: Determie whether PDK4 ablation or inhibition reduces obesity-induced prostatic hyperplasia and inflammation in vivo. Aim 3: Determine whether insulin inhibits prostate fatty acid oxidation in diabetic mice. Based on preliminary data, it is expected that prostate insulin insensitivity increases PDK4 levels and fatty acid flux, leading to hyperplasia, inflammation and resistance to therapy in BPH.

描述（由申请人提供）：本提案的总体目标是发展我的技术和专业能力，成为顶级学术机构的独立研究者，能够为我追求系统之间的分子联系提供完全支持的研究环境。代谢应激和慢性泌尿生殖功能障碍。这将通过一个科学项目来实现，该项目将确定全身代谢改变如何影响局部前列腺代谢和分化。我将继续培育坚强与流行病学家、糖尿病学家和分子生物学家建立跨学科关系，以利用我们实验室开发的基质-上皮相互作用的新模型。为了实现这些目标，我将参加 NIH/MMPC/NIDDK、范德比尔特大学医学中心生物医学研究和培训办公室以及范德比尔特临床培训和研究所提供的研究培训活动。其中包括关于小鼠和代谢研究、生物统计学和蛋白质组学分析的实验模型的会议。范德比尔特糖尿病和研究培训中心还结合其丰富、培训和外展计划提供资助机会、会议和研讨会。其他职业发展机制将包括在全国肥胖、糖尿病和泌尿外科会议上举办的指导性研讨会、拨款和稿件准备以及学术工作面试方面的指导。咨询委员会将评估我的科学和职业发展里程碑的完成情况，并促进我向独立研究者的过渡。良性前列腺增生和相关的下尿路症状（BPH/LUTS）是一种严重的身体和经济负担，考虑到它们与衰老和代谢功能障碍的相关性，其患病人数将继续增加。此外，BPH/LUTS 的临床治疗在疗效上已达到限制，这主要是由于对肥胖和糖尿病患者的治疗抵抗机制了解甚少。需要更多地关注控制前列腺分化和免疫调节的基本代谢机制，以确定预防肥胖和糖尿病患者良性生长和炎症的新靶标。根据我们对小鼠和人类的初步研究，我假设胰岛素调节的碳水化合物/脂肪酸通量是前列腺组织相互作用驱动的分化程序的关键介质，肥胖和 II 型糖尿病破坏了这种稳态，导致肥大和炎症。本研究的具体目的如下：目的1：确定基底细胞脂肪酸氧化是否抑制管腔上皮分化。目标 2：确定 PDK4 消除或抑制是否能减少肥胖引起的体内前列腺增生和炎症。目标 3：确定胰岛素是否抑制糖尿病小鼠的前列腺脂肪酸氧化。根据初步数据，预计前列腺胰岛素不敏感会增加 PDK4 水平和脂肪酸通量，导致 BPH 增生、炎症和治疗耐药。