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

• 批准号: 8633558
• 负责人: Douglas William Strand
• 金额: $ 8.99万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-17 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8633558
• 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; Chronic; Clinical; Clinical Management; Data; Development; Diabetes Mellitus; Diabetic mouse; Diet; Diffusion; Disease; Down-Regulation; Enrollment; Environment; Epidemiologist; Epidemiology; Epithelial; Epithelial-Stromal Communication; Epithelium; Experimental Models; Fatty Acids; Fatty acid glycerol esters; Fostering; Functional disorder; Funding Opportunities; Gene Targeting; Genes; Genetic Markers; Genitourinary system; Goals; Grant; Growth; Healthcare Systems; Homeostasis; Human; Hyperplasia; Hypertrophy; Implant; In Vitro; Inbred NOD Mice; Incidence; Inflammation; Inflammatory; Institutes; Institution; 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 Activity; Training Programs; Transgenes; United States National Institutes of Health; Urology; base; career development; diabetic; diabetic patient; fatty acid metabolism; fatty acid oxidation; feeding; flexibility; glucose uptake; immunoregulation; improved; in vivo; insight; insulin sensitivity; lower urinary tract symptoms; meetings; men; mouse model; novel; outreach program; prevent; programs; public health relevance; pyruvate dehydrogenase kinase 4; resistance mechanism; therapy resistant; three-dimensional modeling; traditional therapy; uptake

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，成为一流学术机构的独立研究者，能够为我追求全身性代谢应激和慢性泌尿生殖功能障碍之间的分子联系提供充分的支持研究环境。这将通过一个科学项目来实现，该项目将确定系统性代谢改变如何影响局部前列腺代谢和分化。我将继续培养坚强