Obesity, Inflammation and BPH

描述(由申请人提供)：我们的总体方法是聚集一个多学科团队来确定肥胖在良性前列腺增生症(BPH)发展中的作用。该研究团队在泌尿生殖道疾病的生物建模、流行病学和医学方面拥有专业知识，特别强调肥胖症、炎症和代谢应激的模型开发和临床表现。总体假设是前列腺良性增生性生长和相关的炎症反应受肥胖和饮食的影响。我们进一步假设，这些变化中的一些可能通过适当的饮食或手术干预而逆转，而另一些则可能变得固定。该项目分为三个目标，都集中在BPH、炎症和肥胖之间的联系上。第一个目标是检测高脂/高蔗糖或高脂/高玉米淀粉饮食方案诱导的野生型、瘦素受体基因敲除(ob/ob)和低密度脂蛋白受体基因敲除(LDLR-/-)C57/BL6小鼠的前列腺组织病理学改变、免疫/炎症细胞募集和全身炎症标志物的变化。我们的初步数据表明，这些模型经历了与人类BPH相一致的前列腺变化。第二个目标将通过热量限制和Roux-en-Y胃分流术(RYGB)检查这些表型和炎症改变的可逆性。这些技术将在炎症和增生发生的特定时间应用于小鼠模型，以确定通过改变饮食习惯可以逆转疾病过程的哪些方面。第三个目标将利用NIDDK支持的对男性BPH患者的前瞻性流行病学研究(纳什维尔男性健康研究)，以确定肥胖和炎症的血液和尿液生物标记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症状随时间的进展有关。具体目标一和二旨在确定肥胖在诱导和维持前列腺增生的特定标记物中的作用。目的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。这些目标在小鼠模型和人类流行病学中的整合以及重叠的生物标记物小组将使小鼠模型适应人类BPH的临床现实，同时也发展了对疾病发病机制的理解。

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.