Acute and Chronic Afferent Engagement: Sympathetic and End Organ Responses

这是由位于宾夕法尼亚州赫尔希的宾夕法尼亚州立大学医学院的四位研究人员向NHLBI提交的一项计划项目拨款的重新提交。所有的调查者都是高效率的科学家。所有的项目负责人都是合作的，所有人都将从这个项目中受益匪浅。我们认为该应用符合PPG的标准，因为：1)有一个统一的主题，即{外周动脉疾病（PAD）加重自主反射反应。将采用两种肢体缺血模型：a)人类受试者的PAD（项目1和项目4）；b)大鼠后肢动脉闭塞（项目2和项目3）}；2)在心血管生理学和病理生理学领域取得重要进展的项目之间存在概念上的协同作用；3)该PPG具有可在前5年资助期内完成的广泛定义的目标；4)提出的许多想法和概念都是项目负责人之前合作的直接结果。Sinoway博士将担任PPG项目主任（PD）。他拥有丰富的科学和管理经验，自1996年起担任Penn State General Clinical Research Center （GCRC）的PD，自2004年起担任PPG的PD。在项目1中，sinway博士将研究运动加压反射（EPR）{在PAD患者肌肉活动期间调节血压的作用。他将研究氧化应激在改变PAD患者反射效应中的作用。在Project 2中，李博士将确定后肢动脉闭塞（大鼠模型）是否会导致DRG神经元P2X、TRPV1和ASIC通道的上调。李博士还将研究神经生长因子（NGF）在这种反应中的作用。在Project 3中，Dr. Kaufman将在大鼠后肢动脉闭塞模型中检测III组和IV组肌肉收缩期间的传入放电{。在项目4中，Leuenberger博士将研究间歇性缺氧（一种有效的氧化应激）在改变正常人和以氧化应激为特征的疾病（包括PAD）患者的交感神经反射和血管扩张剂反应中所起的作用。提出了两个核心：1)核心A将是行政的；2)核心B将是人体生理学核心。

This is a resubmission of a program project grant to the NHLBI by {four} investigators located within the College of Medicine of the Pennsylvania State University in Hershey, Pennsylvania. All investigators are highly productive scientists. All project leaders are collaborative and all will greatly benefit from this program. We believe this application fulfills the criteria for a PPG because: 1) there is a unifying theme namely that {peripheral arterial disease (PAD) accentuates autonomic reflex responses. Two models of limb ischemia will be employed: a) PAD in human subjects (Projects 1 and 4); and b) hindlimb arterial occlusion in rats (Projects 2 and 3)}; 2) conceptual synergy exists between the projects that will lead to important advances in cardiovascular physiology and pathophysiology; 3) this PPG has broadly defined goals that can be accomplished within the first 5 year funding period; and 4) many of the ideas and concepts proposed are a direct result of previous collaborations between the project leaders. Dr. Sinoway will be the PPG Program Director (PD). He has substantial scientific and administrative experience, serving as the PD of the Penn State General Clinical Research Center (GCRC) since 1996, and PD of a PPG since 2004. In Project 1, Dr. Sinoway will examine the role the exercise pressor reflex (EPR) {plays in regulating blood pressure during muscular activity in patients with PAD.} He will examine the role oxidative stress plays in altering reflex effects in PAD patients. In Project 2, Dr. Li will determine if hindlimb arterial occlusion (rat model) leads to upregulation of P2X, TRPV1 and ASIC channels in dorsal root ganglion (DRG) neurons. Dr. Li will also examine the role nerve growth factor (NGF) plays in this response. In Project 3, Dr. Kaufman will examine group III and IV muscle afferent discharge {during contraction in rats with the hindlimb arterial occlusion model.} In Project 4, Dr. Leuenberger will examine the role intermittent hypoxia, a potent oxidative stress, plays in altering sympathetic reflexes and vasodilator responsiveness in {normal humans and those with diseases characterized by oxidative stress including PAD. Two cores are proposed: 1) Core A will be administrative; and 2) Core B will be a human physiology core.