Central regulation of atherosclerosis by testosterone-deficiency

睾酮缺乏对动脉粥样硬化的中枢调节

基本信息

批准号：
10281872
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
项目类别：
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/10281872
关键词：
Ablation Address 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 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 Magnetic Resonance Imaging Mediator of activation protein 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 Predisposition Prevention Prevention strategy Program Development Property Proprotein Convertases 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 base blood glucose regulation cardiometabolic risk cardiometabolism cardiovascular disorder risk cardiovascular risk factor career development deprivation designer receptors exclusively activated by designer drugs dietary energy balance excessive weight gain experimental study feeding glial activation high risk hormone therapy in vivo liver inflammation macrophage male men mouse model multidisciplinary mutant novel nutrition overexpression professor response skills systemic inflammatory response testosterone replacement therapy tool western diet

项目摘要

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项为期4年的研究职业发展计划，重点是大脑机制哪些性别立体侵犯了动脉粥样硬化。候选人目前是研究助理教授华盛顿大学代谢，内分泌学和营养部医学系（UW）。拟议的实验和教学工作将为候选人提供一套独特的多种多样他成为心血管领域的独立调查员的纪律技能。候选人有在智利大学获得了药理学博士学位，并在OHSU完成了两项博士后奖学金和UW。该应用在性类固醇生物学和中枢神经系统新陈代谢方面的专业知识的结合独特的资格使他有资格进行这些研究。在此提案中，他将解决该领域的关键问题心血管疾病，其答案将增加我们对雄激素缺乏和心脏代谢风险升高。 Dorfman博士及其导师（Karin E. Bornfeldt博士和Joshua P. Thaler）制定了一个特定的培训计划，以利用智力资源在UW，指导他完成拟议的教育活动和研究。当前工作的目标是在鼠标模型中进行工作，以识别中枢神经系统的机制，通过这种机制，降压性增加了心血管事件。特别是，他将研究神经胶质细胞（小胶质细胞和星形胶质细胞）在心脏代谢变化加速了动脉粥样硬化的进展。该提议着重于人类证据表明，低循环雄激素会促进心脏代谢失调，并且下丘脑神经胶质性与男性中的内源性睾丸激素和血浆LDL有关。此外，初步数据确定下丘脑神经胶质病的急剧协同性增加由cast割和西方型饮食诱导；在这个动物模型中，早期标记心脏代谢风险也是证据，包括增加肝脏注射和甘油三酸酯含量，转变朝着非常低密度的脂蛋白物种和循环白细胞增多症。这些发现支持研究在特定目标1中提出的是使用将小胶质细胞或星形胶质细胞注入的动物模型确定西方型饮食和雄激素缺乏需要下丘脑神经胶质的协同易感性动脉粥样硬化。此外，候选人已经开发并验证了鼠标小胶质细胞和星形胶质细胞可以通过使用设计师来激活药理学的模型被设计师药物（Dreadd）技术专门激活的受体。这些胶质激活模型提供一个工具来确定神经胶质的足以增加AIM 2中提出的CVD风险。