CNS PPARg, stress, and cardiovascular disease

描述(申请人提供)：该职业发展奖将支持Karen Ryan博士在新陈代谢疾病领域的继续培训，重点是心血管生理学和应激神经生物学，并将促进她向独立的过渡。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，专注于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。这是一个研究不足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，对急性应激源的夸大生理反应也与不良的心血管结果有关。然而，将心理应激与心血管疾病联系起来的具体机制仍未得到解释，尽管这对理解和治疗心血管疾病有重要意义。初步数据表明，通过脂质激活的核受体PPARGamma发出的信号有效地抑制了大鼠对急性心理应激的心血管和HPA反应。此外，PPARGamma信号减弱了下丘脑室旁核(PVH)早期神经元的激活。虽然PPARGamma在PVH和其他大脑区域表达，对心血管和荷尔蒙的应激反应至关重要，虽然PPARgama信号与大鼠和人类心血管指数的改善有关，但几乎不知道大脑PPARGamma在综合应激反应或慢性应激诱导的心血管功能障碍中的作用。这一建议将检验中枢神经系统PPARGamma信号是生理应激反应的组成部分的总体假设，并在钝化长期应激所产生的心血管和内分泌病理方面发挥重要作用。我计划通过追求三个具体目标来检验总体假设。SA1是为了验证这样一个假设，即由药理激动剂和/或内源性脂质激动剂激活PPARγ，会钝化心血管和HPA对急性应激的反应。SA2是为了检验这样一个假设，即激活PPAR伽马可以钝化对慢性可变应激(CVS)的不良全身和心血管反应。这些目标将在指导阶段完成，将促进新技术的培训。职业发展活动包括学术和编写补助金的课程工作，以及与职业咨询委员会(CAC)的定期会议。SA3是为了验证这样一个假设，即中枢神经系统PPARGamma信号足以钝化对应激的急性反应，以及对CVS的不良全身和心血管反应。这一目标建立在瑞安博士在大脑PPAR伽马系统方面的博士后工作以及她将在指导阶段接受的培训的基础上。CAC将继续担任积极的导师，这一角色包括为Ryan博士的第一份R01报告提供建设性的批评。

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.