Mechanisms of Fatty Acid Metabolism in Prostate Differentiation and Disease

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，成为一个独立的研究者在一个顶级的学术机构，能够提供一个完全支持的研究环境，我追求的全身代谢应激和慢性泌尿生殖功能障碍之间的分子联系。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。我会继续培养坚强的 与流行病学家，糖尿病学家和分子生物学家的跨学科关系，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，我将参加由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。其中包括关于代谢研究、生物统计学和蛋白质组学分析的小鼠和实验模型的会议。该范德比尔特糖尿病和研究培训中心还提供资助的机会，会议和研讨会结合其丰富，培训和推广计划。其他的职业发展机制将包括在肥胖症、糖尿病和泌尿学国家会议上举办的指导性研讨会，在赠款和手稿准备方面的指导性指导，以及学术工作面试。一个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）是严重的身体和经济负担，鉴于其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的临床管理已达到疗效的限制，主要是由于对肥胖和糖尿病患者的治疗抵抗机制的理解不足。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点。基于我们在小鼠和人类中的初步研究，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导剂，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：确定是否基底细胞脂肪酸氧化抑制管腔上皮分化。目的2：确定PDK 4消融或抑制是否减少体内肥胖诱导的前列腺增生和炎症。目的3：确定胰岛素是否抑制糖尿病小鼠前列腺脂肪酸氧化。基于初步数据，预期前列腺胰岛素不敏感性增加PDK 4水平和脂肪酸通量，导致BPH中的增生、炎症和对治疗的抵抗。

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.