Acute and Chronic Afferent Engagement: Sympathetic and End Organ Responses

急性和慢性传入参与：交感神经和终末器官反应

基本信息

批准号：
10117087
负责人：
Marc Peter Kaufman
金额：
$ 186.15万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-02-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10117087
关键词：
Acute Animal Model Animals Base Sequence Blood Blood Circulation Blood Pressure Blood Vessels Blood flow Cardiac Cardiovascular Physiology Cardiovascular system Cells Cerebral Atheroscleroses Chronic Clinical Sciences Code Complementary DNA Coronary Coronary Arteriosclerosis Dependence Disease Distal Exercise Functional disorder Funding Gastrocnemius Muscle Goals Hindlimb In Vitro Inflammatory Institutes Intermittent Claudication Laboratories Life Limb structure Medicine Messenger RNA Metabolism Modeling Muscle Muscle Contraction National Heart, Lung, and Blood Institute Neurons Organ Oxidative Stress Oxygen Patients Pennsylvania Peripheral Peripheral arterial disease Play Program Research Project Grants Prostaglandin-Endoperoxide Synthase Proteins Rattus Reflex action Research Personnel Reverse Transcriptase Polymerase Chain Reaction Rodent Role Scientist Sensory Signal Transduction Skeletal Muscle Small Interfering RNA Tissues Transfection Translational Research United States National Institutes of Health Universities WFDC2 gene Western Blotting artery occlusion autonomic reflex clinically significant college cytokine design experience glycogen metabolism human subject in vivo knock-down limb ischemia prevent programs receptor response synergism

项目摘要

PROJECT SUMMARY/ABSTRACT – OVERALL This is a new application of a program project grant to the NHLBI by three investigators located within the College of Medicine of the Pennsylvania State University in Hershey, Pennsylvania. All investigators are highly productive scientists. All Project and Core 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 the exercise pressor reflex (EPR) is accentuated in peripheral artery disease (PAD) and this accentuation has significant cardiovascular consequences. Two models of limb ischemia will be employed to explore this reflex: (a) PAD in human subjects (Project 1); 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 5 year funding period; and 4) many of the ideas and concepts proposed are a direct result of previous interactions 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 NIH funded Clinical and Translational Science Institute at Penn State, and PD of a PPG from 2004 to 2016. In Project 1, Dr. Sinoway will examine the cardiovascular consequences of an accentuated exercise pressor reflex in human subjects with PAD and intermittent claudication. He will examine the impact the accentuated reflex has on the peripheral and cardiac circulations. In Project 2, Dr. Li will examine the role pro-inflammatory cytokines play in altering the blood pressure response to hindlimb contraction after hindlimb arterial occlusion. He will also examine how pro-inflammatory cytokines alter signal transduction in DRG neurons of these animals. In Project 3, Dr. Kaufman will examine the role EP4, ASIC3 and P2X3 receptors on DRG neurons play in accentuating the pressor reflex to hindlimb contraction in rodents with hindlimb arterial occlusion. Two core laboratories are proposed; an Administrative (Core A) that will oversee all administrative functions and a Transfection Core Laboratory (Core B) that will design effective siRNA sequences and provide cDNA clones that code for these `short hairpin' nucleotide sequences, perform the in vivo and in vitro transfection of DRG (L4-L5) and gastrocnemius muscle, and verify protein knockdown employing quantitative RT-PCR (mRNA levels) and Western blotting (protein quantification).

项目概要/摘要——总体这是由位于 NHLBI 的三名研究人员向 NHLBI 申请的一项计划项目拨款的新申请。位于宾夕法尼亚州赫尔希的宾夕法尼亚州立大学医学院所有研究人员都高度评价。所有项目和核心领导者都是富有成效的科学家，所有人都将从中受益匪浅。我们相信该应用程序满足 PPG 的标准，因为： 1) 有一个统一的主题，即运动加压反射 (EPR) 在外周动脉疾病 (PAD) 中加重，并且这种加重将采用两种肢体缺血模型来探讨这一点。反射：(a) 人类受试者的 PAD（项目 1）；以及 (b) 大鼠的后肢动脉闭塞（项目 2 和 3）；这些项目之间存在概念上的协同作用，这将导致心血管领域的重要进展生理学和病理生理学；3) 该 PPG 具有可在 5 年内实现的广泛定义的目标年资助期；4）提出的许多想法和概念都是以前的直接结果项目负责人之间的互动。Sinoway 博士将担任 PPG 项目总监 (PD)。丰富的科学和管理经验，担任 NIH 资助的临床和临床研究的 PD 宾夕法尼亚州立大学转化科学研究所，2004 年至 2016 年担任 PPG 博士。在项目 1 中，Sinoway 博士将检查人类受试者运动加压反射加剧对心血管的影响患有外周动脉疾病 (PAD) 和间歇性跛行的患者，他将检查增强的反射对周围神经的影响。在项目 2 中，李博士将研究促炎细胞因子在改变中的作用。他还将检查后肢动脉闭塞后血压对后肢收缩的反应。在项目 3 中，促炎细胞因子改变了这些动物 DRG 神经元的信号转导。 Kaufman 将研究 DRG 神经元上的 EP4、ASIC3 和 P2X3 受体在增强后肢动脉闭塞的啮齿类动物后肢收缩的升压反射两个核心实验室是。拟议的行政（核心 A）将监督所有行政职能和转染核心实验室（核心 B）将设计有效的 siRNA 序列并提供编码这些序列的 cDNA 克隆 ‘短发夹’核苷酸序列，进行 DRG (L4-L5) 的体内和体外转染腓肠肌，并使用定量 RT-PCR（mRNA 水平）验证蛋白质敲除蛋白质印迹（蛋白质定量）。

项目成果

期刊论文数量（47）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Functional knockout of the TRPV1 channel has no effect on the exercise pressor reflex in rats.

TRPV1 通道的功能性敲除对大鼠的运动升压反射没有影响。

DOI：
10.1113/jp285267
发表时间：
2023
期刊：
The Journal of physiology
影响因子：
0
作者：
Anselmi,Laura;Ducrocq,GuillaumeP;Ruiz-Velasco,Victor;Stocker,SeanD;Higgins,ShannonP;Kaufman,MarcP
通讯作者：
Kaufman,MarcP

Characteristics of acid-sensing ion channel currents in male rat muscle dorsal root ganglion neurons following ischemia/reperfusion.