Obesity, Inflammation and BPH

肥胖、炎症和良性前列腺增生

• 批准号: 8446620
• 负责人: Simon W Hayward
• 金额: $ 31.2万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-29 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8446620
• 关键词: Obesity; Inflammation; 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.

描述（由申请人提供）：我们的总体方法是汇集多学科团队来确定肥胖在良性前列腺增生（BPH）发展中的作用。研究团队在泌尿生殖道疾病的生物模型、流行病学和医学方面拥有专业知识，特别注重肥胖、炎症和代谢应激的模型开发和临床表现。总体假设是，前列腺的良性增生性生长和相关的炎症反应受到肥胖和饮食的影响。我们进一步假设，其中一些变化可以通过适当的饮食或手术干预来逆转，而其他变化可能会得到修复。该项目分为三个目标，全部集中在前列腺增生、炎症和肥胖之间的联系上。第一个目标将测试高脂肪/高蔗糖或高脂肪/高玉米淀粉饮食方案在野生型、瘦素受体敲除（ob/ob）和低密度脂蛋白受体敲除（LDLR-/-）C57/BL6小鼠中诱导的前列腺组织病理学变化、免疫/炎症细胞募集和全身炎症标志物变化。我们的初步数据表明，这些模型经历的前列腺变化与人类 BPH 的各个方面一致。第二个目标是使用热量限制和 Roux-en-Y 胃绕道手术 (RYGB) 手术检查这些表型和炎症变化的可逆性。这些技术将在炎症和增生发展的特定时间应用于小鼠模型，以确定可以通过改变饮食习惯来逆转疾病过程的哪些方面。第三个目标将利用 NIDDK 支持的针对 BPH 男性的前瞻性流行病学研究（纳什维尔男性健康研究）来确定肥胖和炎症的血液和尿液生物标志物以及胰岛素表达和敏感性是否与前列腺组织炎症水平或 BPH 症状随时间进展相关。具体目标一和二旨在确定肥胖在诱导和维持前列腺增生特定标志物中的作用。目标三将这些概念扩展到人类的肥胖、前列腺组织炎症和前列腺增生症进展。将小鼠模型和人类流行病学的这些目标与重叠的生物标志物组合相结合，将使小鼠模型符合人类 BPH 的临床现实，同时也加深对疾病发病机制的理解。