Cholesterol and Prostate Health

胆固醇和前列腺健康

• 批准号: 8334393
• 负责人: Michael R Freeman
• 金额: $ 36.98万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-16 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8334393
• 关键词: Accounting; Affect; Age; Americas; Benign; Benign Prostatic Hypertrophy; Biochemical; Biochemical Pathway; Bioinformatics; Cancer Cell Growth; Cardiovascular Diseases; Cardiovascular system; Cell Survival; Cholesterol; Cholesterol Homeostasis; Chronic Prostatitis; Clinical Trials; Data; Diagnosis; Disease; Epithelial Cells; FDA approved; Functional disorder; Goals; Growth; Health; Health Care Costs; Human; In Situ; Incidence; Inflammation Mediators; Laboratories; Lead; Lipids; Lower urinary tract; Malignant neoplasm of prostate; Metabolic; Methods; Molecular; Mus; Nature; Office Visits; Pathology; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Physiological; Physiology; Play; Population Study; Premalignant; Process; Prostate; Prostatic; Prostatic Diseases; Public Health; Quality of life; Reporting; Research; Risk; Risk Factors; Role; Serum; Severities; Signal Pathway; Signal Transduction; Symptoms; Testing; Urologic Diseases; Variant; base; chronic pelvic pain; effective therapy; epidemiologic data; ezetimibe; hypercholesterolemia; lower urinary tract symptoms; male; men; novel; pre-clinical; prospective; research study; response

DESCRIPTION (provided by applicant): The origin of benign prostatic disease, such as benign prostatic hyperperplasia (BPH) and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), is poorly understood. The public health burden of these conditions is considerable. Office visits in the US during which BPH is the primary diagnosis exceed 4.4 million yearly, with an associated annual health care cost of $1.1 billion. CP/CPPS, which can affect men of all ages, accounts for 3 million annual office visits, remains largely unexplored using modern molecular approaches, and is without effective therapy. Patients suffering from benign prostatic symptoms report a substantially reduced quality of life, and the relationship between benign disease and prostate cancer is still uncertain. Research into the mechanisms of lower urinary tract dysfunction in males may open new opportunities for therapy, however devising hypotheses involving signal transduction mechanisms targetable with pharmaceutical agents remains challenging because of the lack of information about the relevant biochemical pathways. Epidemiologic data suggest an association between BPH symptoms and cardiovascular disease (CVD). Population studies have also produced evidence that cholesterol-lowering drugs reduce the risk of aggressive prostate cancer, while pre-clinical observations have shown that prostate cancer growth and survival pathways depend in part on cholesterol-sensitive biochemical mechanisms. These data suggest that cholesterol metabolism may play a role in the incidence or severity of lower urinary tract symptoms (LUTS) in men. Using a novel method of raising and lowering of circulating cholesterol in the mouse, our laboratory has provided new evidence that the normal prostate in situ. Prostatic epithelial cells in culture also sense and respond to changes in cholesterol levels in their microenvironment. Our data suggest that hypercholesterolemia may predispose to prostate pathology. In this application, we propose the first systematic analysis of the role of serum cholesterol variation in normal prostate physiology and benign pathology. We hypothesize that hypercholesterolemia can promote pathophysiologic changes that may increase the risk of BPH, CP/CPPS, or premalignant transformations associated with prostate cancer. We will challenge this hypothesis with the following specific aims: (1) Determine the physiologic consequences for the normal prostate of prolonged changes in levels of circulating cholesterol. (2) Determine whether a cholesterol-sensitive signaling network is activated in the prostate in response to prolonged changes in levels of circulating cholesterol, and identify critical nodes in this network. These studies will provide the first mechanistic information about the ability of the prostate to detect changes in circulating cholesterol, and because they employ an FDA-approved cholesterol-lowering compound (ezetimibe), the findings from this project may serve as the basis for prospective clinical trials.

描述（由申请人提供）：良性前列腺疾病，例如良性前列腺增生（BPH）和慢性前列腺炎/慢性盆腔疼痛综合征（CP/CPPS）的起源知之甚少。这些情况造成的公共卫生负担相当大。在美国，每年以 BPH 为主要诊断的就诊人数超过 440 万人次，相关的年度医疗费用为 11 亿美元。 CP/CPPS 可以影响所有年龄段的男性，每年有 300 万人次就诊，现代分子方法在很大程度上尚未对其进行探索，并且没有有效的治疗方法。患有良性前列腺症状的患者报告生活质量大幅下降，良性疾病与前列腺癌之间的关系仍不确定。对男性下尿路功能障碍机制的研究可能会为治疗开辟新的机会，然而，由于缺乏有关相关生化途径的信息，设计涉及药物靶向信号转导机制的假设仍然具有挑战性。 流行病学数据表明 BPH 症状与心血管疾病 (CVD) 之间存在关联。人群研究还提供证据表明，降胆固醇药物可以降低侵袭性前列腺癌的风险，而临床前观察表明，前列腺癌的生长和生存途径部分取决于胆固醇敏感的生化机制。这些数据表明胆固醇代谢可能在男性下尿路症状 (LUTS) 的发生率或严重程度中发挥作用。我们的实验室使用一种提高和降低小鼠循环胆固醇的新方法，提供了原位正常前列腺的新证据。培养中的前列腺上皮细胞也能感知微环境中胆固醇水平的变化并做出反应。我们的数据表明高胆固醇血症可能诱发前列腺病理。在本申请中，我们首次系统分析了血清胆固醇变异在正常前列腺生理学和良性病理学中的作用。我们假设高胆固醇血症可以促进病理生理变化，从而增加 BPH、CP/CPPS 或与前列腺癌相关的癌前转化的风险。我们将通过以下具体目标挑战这一假设：（1）确定循环胆固醇水平长期变化对正常前列腺的生理后果。 (2) 确定前列腺中胆固醇敏感信号网络是否因循环胆固醇水平的长期变化而被激活，并识别该网络中的关键节点。 这些研究将提供关于前列腺检测循环胆固醇变化的能力的第一个机制信息，并且由于它们采用 FDA 批准的降胆固醇化合物（依折麦布），因此该项目的研究结果可以作为前瞻性临床的基础试验。