Cholesterol and Prostate Health

胆固醇和前列腺健康

• 批准号: 8188088
• 负责人: Michael R Freeman
• 金额: $ 43.25万
• 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/8188088
• 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. PUBLIC HEALTH RELEVANCE: Cholesterol, its metabolic derivatives, and the signaling pathways that are affected by cellular concentrations of this lipid, all play a significant role in cancer cell growth and survival, and are well established as mediators of inflammation in the cardiovascular system. We now have evidence that the normal prostate in situ, and prostate epithelial cells in culture, respond to changes in cholesterol in the microenvironment. In this proposal we present a plan for the first systematic analysis of the role of serum cholesterol in normal prostate physiology and benign pathology. Our experimental approach is hypothesis-driven, yet unbiased, and takes advantage of nearly 10 years of study in our lab of the role of cholesterol in signal transduction, systems-level expertise we have acquired in recent studies of benign prostatic disease, and advanced bioinformatics expertise of our collaborators. Our current data indicate that the prostate can sense sustained changes in circulating cholesterol and can mount a physiologic response. The experiments we have proposed will rigorously test this idea. Our primary goal is to determine the nature of this response and, in particular, whether hypercholesterolemia promotes pathophysiologic changes likely to increase the risk of: (1) benign prostatic hyperplasia, (2) chronic prostatitis/chronic pelvic pain syndrome and/or (3) prostate cancer.

描述（由申请人提供）：良性前列腺疾病的起源，例如良性前列腺高性增多（BPH）和慢性前列腺炎/慢性骨盆疼痛综合征（CP/CPP）。这些条件的公共卫生负担很大。在美国，BPH为主要诊断的美国办公访就诊每年超过440万，相关的年度医疗保健费用为11亿美元。 CP/CPP会影响各个年龄段的男性，每年的办公室就诊300万，在很大程度上没有使用现代分子方法来探索，并且没有有效的治疗。患有良性前列腺症状的患者报告的生活质量大大降低，良性疾病与前列腺癌之间的关系仍然不确定。研究男性尿路功能障碍的机制可能为治疗带来新的机会，但是由于缺乏有关相关生化途径的信息，因此设计涉及可用药剂剂目标的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。人口研究还产生了证据表明，降低胆固醇的药物降低了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尿路症状（LUTS）的发病率或严重程度中起作用。我们的实验室采用了一种新型的方法来升高和降低循环胆固醇的方法，提供了新的证据，表明正常的前列腺原位。培养物中的前列腺上皮细胞也感知并应对其微环境中胆固醇水平的变化。我们的数据表明，高胆固醇血症可能易于前列腺病理。在此应用中，我们提出了血清胆固醇变异在正常前列腺生理和良性病理学中的作用的首次系统分析。我们假设高胆固醇血症可以促进病理生理学的变化，从而增加BPH，CP/CPP或与前列腺癌相关的预临床转化的风险。我们将以以下特定目的来挑战这一假设：（1）确定循环胆固醇水平长时间变化的正常前列腺的生理后果。 （2）确定是否会在循环胆固醇水平的长度变化中激活胆固醇敏感的信号网络，并确定该网络中的关键节点。 这些研究将提供有关前列腺检测能力检测循环胆固醇变化的能力的第一个机械信息，并且因为它们采用了FDA批准的降胆固醇降低的化合物（Ezetimibe），因此该项目的发现可能是前瞻性临床试验的基础。 公共卫生相关性：胆固醇，其代谢衍生物以及受这种脂质细胞浓度影响的信号传导途径在癌细胞生长和生存中都起着重要作用，并且在心血管系统中被很好地确立为炎症的介体。我们现在有证据表明，正常前列腺原位和培养物中的前列腺上皮细胞对微环境中胆固醇的变化有反应。在此提案中，我们介绍了一个计划，首先是对血清胆固醇在正常前列腺生理学和良性病理学中的作用的系统分析。我们的实验方法是由假设驱动的，但公正的，它在我们在胆固醇转导中的作用，系统级专业知识中利用了将近10年的研究，我们在最近关于良性前列腺疾病的研究中获得了胆固醇的专业知识，以及我们合作者的先进生物信息学专业知识。我们当前的数据表明，前列腺可以感觉到循环胆固醇的持续变化，并可以增强生理反应。我们提出的实验将严格测试这个想法。我们的主要目标是确定这种反应的性质，特别是高胆固醇血症是否会促进病理生理学的变化可能会增加：（1）良性前列腺增生增生，（2）慢性前列腺炎/慢性前列腺炎/慢性骨盆疼痛综合征和/或（3）前列腺癌。