CNS PPARg, stress, and cardiovascular disease

CNS PPARg、压力和心血管疾病

基本信息

批准号：
8958299
负责人：
Karen Ryan
金额：
$ 23.02万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8958299
关键词：
Acute Adrenal Glands Advisory Committees Agonist Anti-Inflammatory Agents Anti-inflammatory Antidiabetic Drugs Anxiety Area Atherosclerosis Autonomic nervous system Basic Science Blood Pressure Blood Vessels Brain Brain region Cardiovascular Diseases Cardiovascular Physiology Cardiovascular system Cause of Death Chronic Chronic stress Clinical Corticosterone Corticotropin Critiques Data Development Endocrine Etiology Exposure to FOS gene Fatty Acids Fatty acid glycerol esters Functional disorder Future Gene Expression Glucocorticoids Goals Grant Heart Rate Hormonal Human Hypertension Hypothalamic structure Immune system Inflammation Mediators Inflammatory Response K-Series Research Career Programs Lentivirus Vector Ligands Link Lipids Measures Mediator of activation protein Mental Depression Mentors Metabolic Metabolic Diseases Metabolic Syndrome X Metabolic syndrome Neurobiology Neuroendocrinology Neurons Nuclear Receptors Oral Outcome Pathology Peripheral Peroxisome Proliferator-Activated Receptors Phase Physiological Play Process Production Psychological Stress Rattus Reaction Research Research Personnel Risk Factors Role Signal Transduction Site Smooth Muscle Myocytes Stress System Techniques Testing Therapeutic Intervention Thymus Gland Training United States VP 16 Vasomotor Weight Woman Work Writing abstracting acute stress biological adaptation to stress cardiovascular disorder risk career career development endothelial dysfunction glucose metabolism heart rate variability indexing inflammatory marker lipid metabolism meetings men mortality novel paraventricular nucleus psychologic psychological stressor receptor research study response restraint restraint stress rosiglitazone sensor small hairpin RNA stressor

项目摘要

7. Project Summary/Abstract This career development award will support Dr. Karen Ryan’s continued training in the field of Metabolic Diseases, focusing on cardiovascular physiology and stress neurobiology, and will facilitate her transition to independence. Her long-term career goal is to be an independent academic researcher in the field of systems neuroendocrinology, with a focus on elucidating specific mechanisms linking environmental signals with the development of metabolic syndrome and cardiovascular dysfunction. Recent evidence supports depression, anxiety, and chronic stress as contributing risk factors for cardiovascular disease (CVD). This is an understudied but critical area of research, since CVD remains the leading cause of mortality in the US. In addition to chronic psychological conditions, exaggerated physiological reactions to acute stressors have also been linked to poor cardiovascular outcomes. However the specific mechanisms linking psychological stress to CVD remain unexplained, despite significant implications for understanding and treating CVD. Preliminary data demonstrate that signaling by the lipid-activated nuclear receptor, PPAR potently abrogated both cardiovascular and HPA responses to acute psychological stress in rats. Moreover, PPAR signaling blunted early neuronal activation in the paraventricular nucleus of the hypothalamus (PVH). Although PPAR is expressed in the PVH and other brain regions critical to the cardiovascular and hormonal responses to stress, and although PPAR signaling is associated with improvements in indices of CVD in both rats and in humans, virtually nothing is known about the role of brain PPAR in the integrated stress response or in chronic stress- induced cardiovascular dysfunction. This proposal will test the overall hypothesis that CNS PPAR signaling is an integral part of the physiological stress response, and plays a major role to blunt cardiovascular and endocrine pathologies engendered by prolonged stress. I plan to test the overall hypothesis by pursuing three specific aims. SA1 is to test the hypothesis that activation of PPAR , by pharmacological agonists and/or endogenous lipid agonists, blunts cardiovascular and HPA responses to acute stress. SA2 is to test the hypothesis that activation of PPAR blunts the adverse systemic and cardiovascular responses to chronic variable stress (CVS). These aims, to be completed during the mentored phase, will facilitate training in new techniques. Career development activities include academic and grant-writing course-work, as well as regular meetings with the Career Advisory Committee (CAC). SA3 is to test the hypothesis that CNS PPAR signaling is sufficient to blunt acute responses to stress, and the adverse systemic and cardiovascular responses to CVS. This aim builds on Dr. Ryan’s postdoctoral work on the brain PPAR system, and on the training she will receive during the mentored phase. The CAC will remain active mentors, a role that includes providing constructive critiques of Dr. Ryan’s first R01 submission.

7. 项目总结/摘要该职业发展奖将支持 Karen Ryan 博士在代谢领域的继续培训疾病，重点关注心血管生理学和应激神经生物学，并将促进她过渡到她的长期职业目标是成为系统领域的独立学术研究员。神经内分泌学，重点是阐明将环境信号与神经内分泌联系起来的具体机制代谢综合征和心血管功能障碍的发展最近的证据支持抑郁症，焦虑和慢性压力是心血管疾病（CVD）的危险因素。由于心血管疾病仍然是美国死亡的主要原因，因此该领域尚未得到充分研究，但却是一个关键的研究领域。除了慢性心理状况外，对急性压力源的过度生理反应也导致然而，与不良心血管结局有关的具体机制是与心理压力相关的。尽管对理解和治疗 CVD 具有重要意义，但对 CVD 的影响仍然无法解释。数据表明，脂质激活核受体 PPAR 的信号传导可有效消除两者大鼠心血管和 HPA 对急性心理应激的反应此外，PPAR 信号传导减弱。尽管 PPAR 是下丘脑室旁核 (PVH) 的早期神经激活。在 PVH 和其他大脑关键区域中表达，这些区域对心血管和荷尔蒙对压力的反应至关重要，尽管 PPAR 信号传导与大鼠和人类的 CVD 指数改善相关，事实上，人们对大脑 PPAR 在综合应激反应或慢性应激中的作用一无所知。该提案将检验 CNS PPAR 信号传导的总体假设。生理应激反应的一个组成部分，在减弱心血管和我计划通过三个方面来检验总体假设。 SA1 的具体目的是测试通过药理学激动剂和/或激活 PPAR 的假设。内源性脂质激动剂，会减弱心血管和 HPA 对急性应激的反应，以测试 SA2。假设 PPAR 的激活可以减弱对慢性疾病的不良全身反应和心血管反应这些目标将在指导阶段完成，将有助于新的培训。职业发展活动包括学术和资助写作课程以及常规活动。与职业咨询委员会 (CAC) 的会议旨在检验 CNS PPAR 信号传导的假设。足以减弱对压力的急性反应，以及对压力的不良全身和心血管反应 CVS 这一目标建立在 Ryan 博士关于大脑 PPAR 系统的博士后工作以及她将要接受的培训的基础上。 CAC 将继续担任积极的导师，其角色包括提供指导。对 Ryan 博士的第一份 R01 提交的建设性批评。