CNS PPARg, stress, and cardiovascular disease

CNS PPARg、压力和心血管疾病

• 批准号: 8303507
• 负责人: Karen Ryan
• 金额: $ 11.92万
• 依托单位: UNIVERSITY OF CINCINNATI
• 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 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8303507
• 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; PPAR gamma; Pathology; Peripheral; 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; acute stress; biological adaptation to stress; cardiovascular disorder risk; career; career development; 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

DESCRIPTION (provided by applicant): 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, PPARgamma potently abrogated both cardiovascular and HPA responses to acute psychological stress in rats. Moreover, PPARgamma signaling blunted early neuronal activation in the paraventricular nucleus of the hypothalamus (PVH). Although PPARgamma is expressed in the PVH and other brain regions critical to the cardiovascular and hormonal responses to stress, and although PPARgama signaling is associated with improvements in indices of CVD in both rats and in humans, virtually nothing is known about the role of brain PPARgamma in the integrated stress response or in chronic stress- induced cardiovascular dysfunction. This proposal will test the overall hypothesis that CNS PPARgamma 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 PPARgamma, 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 PPARgamma 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 PPARgamma 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 PPARgamma 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.

描述（由申请人提供）：该职业发展奖将支持 Karen Ryan 博士在代谢疾病领域继续接受培训，重点关注心血管生理学和应激神经生物学，并将促进她向独立过渡。她的长期职业目标是成为系统神经内分泌学领域的独立学术研究员，重点是阐明环境信号与代谢综合征和心血管功能障碍的发展之间联系的具体机制。最近的证据支持抑郁、焦虑和慢性压力是心血管疾病 (CVD) 的危险因素。这是一个尚未得到充分研究但至关重要的研究领域，因为心血管疾病仍然是美国死亡的主要原因。除了慢性心理状况外，对急性压力源的过度生理反应也与不良的心血管结局有关。然而，尽管心理压力与 CVD 之间的联系对于理解和治疗 CVD 具有重要意义，但其具体机​​制仍不清楚。初步数据表明，脂质激活核受体 PPARgamma 发出的信号可有效消除大鼠对急性心理应激的心血管和 HPA 反应。此外，PPARgamma 信号传导减弱了下丘脑室旁核 (PVH) 的早期神经元激活。尽管 PPARgamma 在 PVH 和其他对心血管和应激激素反应至关重要的大脑区域中表达，并且尽管 PPARgama 信号传导与大鼠和人类的 CVD 指数的改善相关，但实际上对大脑 PPARgamma 在综合应激反应或慢性应激诱发的心血管功能障碍中的作用一无所知。该提案将检验以下总体假设：CNS PPARgamma 信号传导是生理应激反应的一个组成部分，并且在减弱长期应激引起的心血管和内分泌病理方面发挥着重要作用。我计划通过追求三个具体目标来检验总体假设。 SA1 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激活 PPARgamma，会减弱心血管和 HPA 对急性应激的反应。 SA2 旨在检验以下假设：PPARgamma 的激活会减弱对慢性可变应激 (CVS) 的不良全身和心血管反应。这些目标将在指导阶段完成，将促进新技术培训。职业发展活动包括学术和资助写作课程，以及与职业咨询委员会 (CAC) 的定期会议。 SA3 旨在检验 CNS PPARgamma 信号传导足以减弱对压力的急性反应以及对 CVS 的不良全身和心血管反应的假设。这一目标建立在 Ryan 博士关于大脑 PPARgamma 系统的博士后工作以及她在指导阶段接受的培训的基础上。 CAC 将继续充当积极的导师，其角色包括对 Ryan 博士的第一份 R01 提交内容提供建设性批评。