CNS PPARg, stress, and cardiovascular disease

7.项目摘要/摘要 该职业发展奖将支持Karen Ryan博士在新陈代谢领域的继续培训 疾病，专注于心血管生理学和应激神经生物学，并将促进她过渡到 独立。她的长期职业目标是成为系统领域的一名独立学术研究员 神经内分泌学，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。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。这是一个 研究不足但很关键的研究领域，因为心血管疾病仍然是美国死亡的主要原因。在……里面 除了慢性心理状况外，对急性应激源的夸大生理反应也有 与心血管疾病的不良结局有关。然而，与心理压力有关的具体机制 尽管对理解和治疗心血管疾病有重大影响，但对心血管疾病的认识仍未得到解释。初步 数据表明，由脂质激活的核受体PPAR发出的信号有效地取消了这两种受体 大鼠对急性心理应激的心血管和HPA反应。此外，PPAR信号迟钝 下丘脑室旁核(PVH)神经元的早期激活。尽管PPAR是 在PVH和其他对心血管和荷尔蒙应激反应至关重要的脑区表达， 尽管PPAR信号与大鼠和人类心血管疾病指数的改善有关， 关于大脑PPAR在综合应激反应或慢性应激中的作用，人们几乎一无所知。 导致心血管功能障碍。这一提议将检验CNS PPAR信号是 是生理应激反应中不可或缺的一部分，在钝化心血管和 长期应激引起的内分泌病变。我计划通过追求三个方面来检验整个假说 明确的目标。SA1是为了检验这样一种假设，即药理激动剂和/或 内源性脂质激动剂，钝化心血管和HPA对急性应激的反应。SA2将测试 假设PPAR的激活会钝化慢性疾病的不良全身和心血管反应 可变应力(CVS)。这些目标将在指导阶段完成，将促进新的 技巧。职业发展活动包括学术和编写补助金课程工作，以及定期 与职业咨询委员会(CAC)的会议。SA3是为了检验中枢神经系统PPAR信号的假设 足以钝化对压力的急性反应，以及对 CVS。这一目标建立在瑞安博士在大脑PPAR系统上的博士后工作基础上，以及她将进行的培训 在指导阶段接收。CAC将继续担任积极的导师，这一角色包括提供 对瑞安博士的第一份R01意见书的建设性批评。

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.