Central regulation of atherosclerosis by testosterone-deficiency

睾酮缺乏对动脉粥样硬化的中枢调节

• 批准号: 10680457
• 负责人: Mauricio D Dorfman
• 金额: $ 16.2万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-06 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10680457
• 关键词: Ablation; Acceleration; Androgen Receptor; Androgens; Animal Model; Astrocytes; Atherosclerosis; Attenuated; Autopsy; Biochemical; Biology; Body Composition; Brain; Cardiometabolic Disease; Cardiovascular Diseases; Cardiovascular system; Castration; Cause of Death; Cells; Chile; Chronic; Consumption; Data; Development; Disease Progression; Doctor of Philosophy; Dyslipidemias; Educational Activities; Endocrinology; Event; Fatty Liver; Fellowship; Genetic; Gliosis; Glucose Intolerance; Goals; Gonadal Steroid Hormones; Heart Diseases; High Fat Diet; Histopathology; Human; Hyperlipidemia; Hyperphagia; Hypogonadism; Hypothalamic structure; Incidence; Inflammation; Inflammatory; International; Intervention; Investigation; Leukocytosis; Link; Lipids; Lipoproteins; Liver; Low Density Lipoprotein Receptor; Low-Density Lipoproteins; Macrophage; Magnetic Resonance Imaging; Mediator; Medicine; Mentors; Metabolic; Metabolic Diseases; Metabolic syndrome; Metabolism; Methods; Microglia; Modeling; Monocytosis; Mus; NF-kappa B; Neuroglia; Obesity; Operative Surgical Procedures; Pathway interactions; Peripheral; Pharmacology; Plasma; Play; Postdoctoral Fellow; Predisposition; Prevention; Prevention strategy; Program Development; Property; Proprotein Convertases; Qualifying; Regulation; Research; Research Assistant; Research Personnel; Resources; Risk; Risk Factors; Role; Serum; Signal Transduction; Stroke; Subtilisins; System; Technology; Testing; Testosterone; Training; Triglycerides; United States; Universities; Very low density lipoprotein; Washington; Weight Gain; Work; atherosclerosis risk; blood glucose regulation; cardiometabolic risk; cardiometabolism; cardiovascular disorder risk; cardiovascular risk factor; career development; deprivation; designer receptors exclusively activated by designer drugs; dietary; education research; energy balance; excessive weight gain; experimental study; feeding; glial activation; high risk; hormone therapy; in vivo; liver inflammation; male; men; mouse model; multidisciplinary; mutant; novel; nutrition; overexpression; pharmacologic; professor; response; skills; systemic inflammatory response; testosterone replacement therapy; tool; western diet

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.

项目摘要 该提案描述了一个为期4年的研究职业发展计划，重点是大脑机制， 哪种性类固醇可以防止动脉粥样硬化候选人目前是一个研究助理教授， 华盛顿大学医学系代谢、内分泌和营养学系 （UW）。拟议的实验和教学工作将为候选人提供一套独特的多功能 他的专业技能使他成为心血管领域的独立研究者。这位候选人有 在智利大学获得药理学博士学位，并在OHSU获得两个博士后奖学金 和UW。申请人在性类固醇生物学和CNS代谢调节方面的专业知识相结合 唯一有资格进行这些研究的人在这一建议中，他将讨论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心血管疾病之间关系的理解。 雄激素缺乏和心脏代谢风险升高。Dorfman博士和他的导师（Karin E.博恩费尔特 和约书亚P.塞勒）制定了一个具体的培训计划，利用智力资源， 在华盛顿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症增加 心血管事件。具体来说，他将研究神经胶质细胞（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。该提案侧重于人类 有证据表明，低水平的循环雄激素促进心脏代谢失调， 男性下丘脑神经胶质增生与较低的内源性睾酮和血浆LDL相关。此外，委员会认为， 初步数据表明，当性腺功能减退时， 在该动物模型中，通过阉割和西式饮食诱导的早期标记物 心脏代谢风险也很明显，包括肝脏炎症和甘油三酯含量增加， 非常低密度脂蛋白和循环白细胞增多。这些发现支持了 在具体目标1中提出使用具有小胶质细胞或星形胶质细胞炎症消融的动物模型， 确定下丘脑神经胶质增生是否是西式饮食和雄激素缺乏所必需的， 协同地易患动脉粥样硬化。此外，候选人还开发并验证了一种鼠标 一种模型，其中小胶质细胞和星形胶质细胞可以通过使用设计师被激活 设计药物独家激活受体（DREADD）技术。这些神经胶质激活的模型 提供一种工具来确定胶质增生是否足以增加目标2中提出的CVD风险。