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）：我们的整体方法是将一个多学科的团队汇集在一起​​，以确定肥胖症在良性前列腺增生（BPH）发展中的作用。研究小组在泌尿生殖道疾病，流行病学和医学的生物学建模方面具有专业知识，特别着重于肥胖，炎症和代谢压力的模型开发和临床表现。总体假设是，前列腺和相关炎症反应的良性增生生长受肥胖和饮食的影响。我们进一步假设，其中一些变化可能会因适当的饮食或手术干预而逆转，而其他一些变化可能会固定。该项目分为三个目标，所有目标都集中在BPH，炎症和肥胖之间的联系。第一个目的将测试前列腺组织病理学的变化，免疫/炎症细胞募集和全身性炎症标记物在野生型，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，高脂/高脂肪/高脂肪/高脂肪/高脂肪/高脂肪/高脂肪/高脂肪/高脂肪/高corner corners Meginens sirens sarens sarens sarens stareens sarens sarens sarens sarens sarens sarens sarens sarens sarens。我们的初步数据表明，这些模型经历了与人类BPH方面一致的前列腺变化。第二个目的将检查这些表型和炎症性变化的可逆性，并使用热量限制和roux-en-y胃搭桥手术（RYGB）手术。这些技术将在炎症和增生的发展时在特定时间应用于小鼠模型，以确定疾病过程的哪些方面可以通过改变饮食习惯来逆转。第三个目标将利用BPH男性（纳什维尔男性健康研究）的NIDDK支持的前瞻性流行病学研究来确定肥胖，炎症和炎症表达和敏感性是否与前列腺炎症或BPH症状的水平相关。特定目标一和两个旨在确定肥胖在前列腺增生特定标记的诱导和维持中的作用。目标三将这些概念扩展到肥胖，前列腺组织炎症和人类的BPH进展。这些目的在小鼠模型和人类流行病学与重叠生物标志物面板之间的整合将小鼠模型扎根于人类BPH的临床现实，同时也对疾病发病机理的机制有了了解。