CNS PPARg, stress, and cardiovascular disease

CNS PPARg、压力和心血管疾病

• 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
• 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

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 这个职业发展奖将支持凯伦·瑞安博士在代谢领域的继续培训。 疾病，重点是心血管生理学和应激神经生物学，并将促进她的过渡到 独立她的长期职业目标是成为系统领域的独立学术研究者 神经内分泌学，重点是阐明环境信号与神经内分泌之间的特定机制。 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。这是一 这是一个研究不足但至关重要的研究领域，因为CVD仍然是美国死亡率的主要原因。在 除了慢性心理疾病外，对急性应激源的过度生理反应也 与不良心血管结局有关。然而，将心理压力联系起来的具体机制 尽管对理解和治疗CVD具有重要意义，但CVD的发病机制仍然无法解释。初步 数据表明，脂质激活的核受体信号，过氧化物酶体激活受体有力地废除了这两个 心血管和HPA对急性心理应激的反应。此外， 下丘脑室旁核（PVH）的早期神经元激活。虽然PPARs 在PVH和其他对心血管和激素应激反应至关重要的大脑区域中表达， 尽管在大鼠和人类中，PPAR信号传导与CVD指数的改善相关， 事实上，关于大脑过氧化物酶体增殖物激活受体在综合应激反应或慢性应激中的作用还一无所知- 诱发心血管功能障碍。该提案将检验CNS PPAR信号转导是一种新的信号转导途径的总体假设。 生理应激反应的一个组成部分，并发挥重要作用，钝心血管和 由于长期压力而引起的内分泌疾病。我计划通过以下三个方面来检验整个假设 具体目标。SA 1旨在检验以下假设：通过药理学激动剂和/或 内源性脂质激动剂减弱心血管和HPA对急性应激的反应。SA 2是为了测试 假设激活的过氧化物酶体激活物减弱了不利的全身和心血管反应， 变应力（CVS）。这些目标将在辅导阶段完成， 技术.职业发展活动包括学术和赠款写作课程工作，以及定期 职业咨询委员会（CAC）。SA 3是为了检验CNS PPAR信号转导 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。 栽培变种这一目标建立在Ryan博士关于大脑PPAR系统的博士后工作以及她将接受的培训之上。 在指导阶段接受。CAC将继续发挥积极的导师作用，包括提供 瑞安博士的第一个R 01提交建设性的批评。