Obesity, Inflammation and BPH

肥胖、炎症和良性前列腺增生

• 批准号: 8566167
• 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/8566167
• 关键词: Address; Aging; Benign; Benign Prostatic Hypertrophy; Biological Assay; Biological Markers; Biological Models; Blood; Body Weight decreased; Caloric Restriction; Carbohydrates; Cells; Characteristics; Chronic; Clinical; Clinical Research; Complex; Data; Development; Diabetes Mellitus; Diet; Diet Habits; Dietary Component; Dinoprostone; Disease; Eating; Ensure; Epidemic; Epidemiologic Studies; Epidemiology; Epithelium; F2-Isoprostanes; Fatty acid glycerol esters; Genetic; Genitourinary system; Goals; Growth; Healthcare; Human; Hyperlipidemia; Hyperplasia; Immune; Inflammation; Inflammatory; Inflammatory Response; Insulin; Insulin Resistance; Knock-out; Link; Low Density Lipoprotein Receptor; Maintenance; Measures; Medicine; Metabolic; Metabolic stress; Methods; Modeling; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Obesity; Operative Surgical Procedures; Oxidative Stress; Pathogenesis; Patients; Play; Process; Prostate; Prostatic; Prostatic Diseases; Prostatic hypertrophy; Regimen; Research; Resolution; Resources; Role; Serum; Severities; Stress; Sucrose; Symptoms; Techniques; Testing; Time; Tissues; United States; Urine; Weight; Work; adiponectin; bariatric surgery; design; dietary starch; feeding; human disease; in vivo Model; inflammatory marker; lower urinary tract symptoms; male health; men; model development; mouse model; multidisciplinary; prospective; prostaglandin M; receptor; response

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, infiammation, and metabolic stress. The overall hypothesis is that benign hyperplastic growth of the prostate and associated infiammatory responses are influenced by obesity and diet. We further hypothesize that some of these changes may be reversed by appropriate dietary or surgical intervenfions, while others may become fixed. The project is broken into three aims, all centered on the links between BPH, infiammafion, and obesity. The first aim will test prostafic histopathologic changes, immune/inflammatory cell recruitment and systemic inflammatory marker changes induced in wild type, lepfin 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 infiammatory changes using caloric restriction and Roux-en-Y gastric bypass (RYGB) surgery. These techniques will be applied to the mouse models at specific fimes 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 infiammafion and insulin expression and sensifivity are associated with levels of prostate tissue inflammation or BPH symptom progression over time. Speciflc 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 infiammation, and BPH progression in humans. The integrafion of these aims across mouse models and human epidemiology with overlapping biomarker panels will ground the mouse models to the clinical realifies of human BPH, while also developing an understanding of the mechanisms underiying disease pathogenesis.

我们的总体方法是汇集一个多学科的团队，以确定肥胖的作用， 良性前列腺增生（BPH）的发展。该研究团队拥有生物建模方面的专业知识 泌尿生殖道疾病，流行病学和医学，特别强调模型的发展， 肥胖、炎症和代谢应激的临床表现。 总的假设是前列腺的良性增生性生长和相关的炎性细胞因子， 反应受肥胖和饮食的影响。我们进一步假设，其中一些变化可能是 通过适当的饮食或手术干预可以逆转，而其他人可能会变得固定。该项目 分为三个目标，都集中在前列腺增生，炎症和肥胖之间的联系。第一个目标将 试验性组织病理学变化、免疫/炎症细胞募集和全身炎症 在野生型、瘦素受体敲除（ob/ob）和低密度脂蛋白受体中诱导的标志物变化 通过高脂肪/高蔗糖或高脂肪/高玉米淀粉饮食方案对敲除（LDLR-/-）C57/BL 6小鼠进行的研究。我们 初步数据表明，这些模型经历的前列腺变化与 人类前列腺增生症。第二个目的是研究这些表型和炎症变化的可逆性 使用热量限制和Roux-en-Y胃旁路术（RYGB）。这些技术将应用于 小鼠模型在炎症和增生发展的特定时间，以确定 通过改变饮食习惯可以逆转疾病的某些方面。第三个目标将发挥作用 NIDDK支持的BPH男性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志物以及胰岛素表达和敏感性， 与前列腺组织炎症水平或BPH症状随时间的进展有关。具体 目的一和二旨在确定肥胖在诱导和维持特定的 前列腺增生的标志物。目的三将这些概念扩展到肥胖、前列腺组织炎症， 和人类BPH的进展。这些目标在小鼠模型和人类模型中的整合 具有重叠生物标志物组的流行病学将使小鼠模型与以下临床实现相结合： 人类BPH，同时也发展了对疾病发病机制的理解。