Biomarkers of Obesity, Prostate Tissue Inflammation, and BPH Progression

描述（由申请人提供）：肥胖增加细胞因子水平并产生慢性氧化应激状态，这可能促进前列腺组织炎症。一些先前的前瞻性研究报告肥胖与良性前列腺增生（BPH）的临床症状有关。然而，肥胖和前列腺组织炎症之间的关系仍然不清楚，肥胖引起的炎症和氧化应激的相关性尚未确定。我们的目标是首先确定肥胖（BMI，腰围，腰臀比，生物电阻抗分析的体脂%）是否与500名无前列腺癌或前列腺上皮内瘤形成的男性前列腺活检组织中的炎性白细胞计数和炎症严重程度相关。我们还将研究前列腺炎症与四种有希望和经验证的炎症和氧化应激生物标志物（尿前列腺素E2（PGE-M）和F2-异前列烷（F2 iP-M）代谢物）以及血液脂联素和C-反应蛋白（CRP）水平之间的相关性，这些生物标志物可能介导肥胖对BPH进展的影响。我们还将描述肥胖和NF-κ B活性诱导两种肥胖小鼠模型（ob/ob和agglutination）前列腺增生的机制。为了描述肥胖对BPH进展的临床影响，我们将前瞻性地随访研究参与者的下尿路症状变化和BPH治疗的开始。采用多变量线性、逻辑和考克斯回归分析，我们将描述肥胖、脂联素、PGE-M、CRP和F2 iP-M水平与前列腺组织炎症指数、症状严重程度变化和BPH进展之间的相关性。我们的方法是新颖的，多学科的，和翻译;并将更快地导致新的见解，在前列腺组织炎症和BPH进展的病因和临床作用的肥胖。结果可能会争论针对肥胖，炎症或氧化应激的几种合理干预措施之一，以延缓BPH进展。

DESCRIPTION (provided by applicant): Obesity increases cytokine levels and generates a state of chronic oxidative stress that may facilitate prostate tissue inflammation. Several prior prospective studies report obesity is associated with clinical symptoms of benign prostatic hyperplasia (BPH). However, the relationship between obesity and prostate tissue inflammation remains unclear, and the relevance of obesity-induced inflammation and oxidative stress is undetermined. Our goal is first to determine if obesity (BMI, waist circumference, waist-hip ratio, % body fat from bioelectric impedance analysis) is associated with inflammatory leukocyte cell count and inflammation severity in prostate biopsy cores from 500 men without prostate cancer or prostatic intraepithelial neoplasia. We will also investigate the association between prostate inflammation and four promising and validated biomarkers of inflammation and oxidative stress (urine prostaglandin E2 (PGE-M) and F2-isoprostane (F2iP-M) metabolites), and blood adiponectin and C-reactive protein (CRP) levels, that may mediate the effects of obesity on BPH progression. We will also characterize the mechanisms by which obesity and NF-kB activity induce the development of prostate hyperplasia in two mouse models of obesity (ob/ob and agouti). To describe the clinical impact of obesity on BPH progression, we will then prospectively follow study participants for changes in lower urinary tract symptoms and initiation of BPH treatment. Using multivariable linear, logistic, and COX regression, we will describe the associations between obesity, adiponectin, PGE-M, CRP, and F2iP-M levels with indices of prostate tissue inflammation and changes in symptom severity and BPH progression. Our approach is novel, multi-disciplinary, and translational; and will more rapidly lead to new insights into the etiologic and clinical roles of obesity in prostate tissue inflammation and BPH progression. Results may argue for one of several plausible interventions targeting obesity, inflammation, or oxidative stress to delay BPH progression.