Central regulation of atherosclerosis by testosterone-deficiency

项目摘要 这项提案勾勒出了一个为期4年的研究职业发展计划，重点是大脑机制，通过 性类固醇可以预防动脉粥样硬化。应聘者目前是研究助理教授 华盛顿大学新陈代谢、内分泌学和营养学部医学系 (UW)。拟议的实验和教学工作将为考生提供一套独特的多学科 纪律技能使他成为心血管领域的一名独立调查员。候选人有 在智利大学获得药理学博士学位，并在俄亥俄州立大学获得两个博士后奖学金 和威斯康星州。申请人在性类固醇生物学和中枢神经系统新陈代谢调节方面的专业知识 使他有资格进行这些研究。在这项提案中，他将解决以下领域的关键问题 心血管疾病，这些问题的答案将增加我们对 雄激素缺乏和心脏代谢风险增加。多夫曼博士和他的导师(卡琳·E·伯恩菲尔特博士 和约书亚·P·泰勒)制定了一项利用智力资源的具体培训计划 在威斯康星州大学指导他通过拟议的教育活动和研究。当前工作的目标 是在小鼠模型中工作，以确定性腺功能减退增加发病率的中枢神经系统机制 心血管事件。具体地说，他将研究胶质细胞(小胶质细胞和星形胶质细胞)在 加速动脉粥样硬化进展的心脏代谢变化。该提案以人为本 有证据表明，低水平的循环雄激素促进心脏代谢紊乱，而且 男性下丘脑胶质细胞增多症与内源性睾酮和血浆低密度脂蛋白水平降低有关。此外， 初步数据表明，当性腺功能减退时，下丘脑胶质细胞增多症显著增加。 去势诱导和西式饮食相结合；在该动物模型中，早期标志物 心脏代谢的风险也很明显，包括肝脏炎症和甘油三酯含量的增加，这是一个转变 向极低密度脂蛋白和循环白细胞增多症发展。这些发现支持研究 在特定目标1中提出使用消融小胶质细胞或星形胶质细胞炎症的动物模型 确定西式饮食和雄激素缺乏是否需要下丘脑胶质细胞增多症 协同作用易致动脉粥样硬化。此外，候选人还开发并验证了一款鼠标 小胶质细胞和星形胶质细胞可以通过使用Designer药物激活的模型 由特制药物(DREADD)技术独家激活的受体。这些神经胶质细胞激活的模型 提供一种工具来确定胶质细胞增多症是否足以增加目标2中提出的心血管疾病的风险。

Project Summary This proposal delineates a 4-year research career development program focused on brain mechanisms by which sex steroids protect from atherosclerosis. The candidate is currently a Research Assistant Professor in the Department of Medicine, Division of Metabolism, Endocrinology and Nutrition at University of Washington (UW). The proposed experiments and didactic work will provide the candidate with a unique set of multi- disciplinary skills for him to become an independent investigator in the cardiovascular field. The candidate has completed a PhD degree in Pharmacology at the University of Chile and two postdoctoral fellowships at OHSU and UW. The applicant’s combination of expertise in sex steroids biology and CNS regulation of metabolism uniquely qualify him to conduct these studies. In this proposal, he will address key questions in the field of cardiovascular disease, the answers to which will increase our understanding of the relationship between androgen deficiency and elevated cardiometabolic risk. Dr. Dorfman and his mentors (Drs. Karin E. Bornfeldt and Joshua P. Thaler) have created a specific training plan that takes advantage of the intellectual resources at the UW to guide him through the proposed educational activities and research. The goal of the current work is to work in mouse models to identify CNS mechanisms by which hypogonadism increases the incidence of cardiovascular events. Specifically, he will investigate the role of glial cells (microglia and astrocytes) in cardiometabolic changes that accelerate the progression of atherosclerosis. The proposal focuses on human evidence that low levels of circulating androgens promotes cardiometabolic dysregulation, and that hypothalamic gliosis is associated with lower endogenous testosterone and plasma LDL in men. Furthermore, the preliminary data identify a dramatic synergistic increase of hypothalamic gliosis when hypogonadism induced by castration and Western-type diet are combined; in this animal model, early markers of cardiometabolic risk are also evident including increased liver inflammation and triglyceride content, a shift toward very low density lipoprotein species, and circulating leukocytosis. These findings support studies proposed in Specific Aim 1 to use animal models with ablation of microglial or astrocyte inflammation to determine whether hypothalamic gliosis is required for Western-type diet and androgen deficiency to synergistically predispose to atherosclerosis. Additionally, the candidate has developed and validated a mouse model in which microglia and astrocytes can be pharmacologically activated through the use of Designer Receptors Exclusively Activated by Designer Drugs (DREADD) technology. These models of glial activation provide a tool to determine whether gliosis is sufficient to increase the risk of CVD as proposed in Aim 2.