Cholesterol and Prostate Health

描述（由申请人提供）：良性前列腺疾病，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）的起源尚不清楚。这些疾病造成的公共卫生负担相当大。在美国，以BPH为主要诊断的办公室就诊人数每年超过440万，相关的年度医疗保健费用为11亿美元。CP/CPPS可影响所有年龄段的男性，每年约有300万人次就诊，使用现代分子方法在很大程度上仍未被探索，也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大降低，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为治疗开辟新的机会，然而，由于缺乏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。流行病学数据表明前列腺增生症状与心血管疾病（CVD）之间存在关联。人口研究也有证据表明，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依赖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。利用一种提高和降低小鼠循环胆固醇的新方法，我们的实验室提供了新的证据，证明正常前列腺在原位。培养的前列腺上皮细胞也能感知并响应微环境中胆固醇水平的变化。我们的数据表明高胆固醇血症可能导致前列腺病变。在这个应用中，我们提出了血清胆固醇变化在正常前列腺生理和良性病理中的作用的第一个系统分析。我们假设高胆固醇血症可以促进病理生理变化，可能增加BPH、CP/CPPS或与前列腺癌相关的癌前转化的风险。我们将以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)确定胆固醇敏感信号网络是否在前列腺中被激活，以响应循环胆固醇水平的长期变化，并确定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能力的第一个机制信息，并且因为他们使用了fda批准的降胆固醇化合物（依折替米贝），这个项目的发现可能作为前瞻性临床试验的基础。

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.