Central Rho-Kinase Inhibition and Ang II-induced Sympatho-excitation

中枢 Rho 激酶抑制和 Ang II 诱导的交感兴奋

• 批准号: 8932603
• 负责人: Peter Ricci Pellegrino
• 金额: $ 3.92万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8932603
• 关键词: Acute; Address; Angiotensin II; Animals; Atropine; Attenuated; Baroreflex; Biological Availability; Brain; Brain Stem; Cardiac; Cell Line; Cell Nucleus; Chronic; Chronic Kidney Failure; Clinic; Clinical; Clinical Medicine; Congestive Heart Failure; Conscious; Disease; Doctor of Medicine; Doctor of Philosophy; Educational workshop; Engineering; Equilibrium; Essential Hypertension; Feedback; Generations; Heart Rate; Heart failure; Hypertension; Hypothalamic structure; In Vitro; Infusion procedures; Ischemic Stroke; Japan; Journals; Kidney; Laboratories; Mediating; Mediator of activation protein; Medical center; Methods; Metoprolol; Modeling; Molecular; Nebraska; Nerve; Neurons; New Zealand; Nitric Oxide; Norepinephrine; Oryctolagus cuniculus; Oxidative Stress; Pathway interactions; Physicians; Physiology; Plasma; Process; Production; Proteins; Reactive Oxygen Species; Regulation; Renin-Angiotensin-Aldosterone System; Research; Rho-associated kinase; Role; Schedule; Scheme; Shadowing (Histology); Signal Transduction; Sympatholytics; System; Tissues; Training; Universities; Writing; design; fasudil; heart rate variability; instrument; interest; kinase inhibitor; novel; overexpression; pressure; programs; public health relevance; pulmonary arterial hypertension; research study; response; rhoA GTP-Binding Protein; statistics; subcutaneous; symposium; therapeutic target

DESCRIPTION (provided by applicant): This application describes a research plan and course of study leading to the Ph.D. degree as part of the M.D./Ph.D. Program at The University of Nebraska Medical Center. The overarching hypothesis of the research plan is that activation of central Rho-kinase by Angiotensin II (Ang II) contributes to sympathoexcitation in disease states (like heart failure, hypertension) and that Rho-kinase inhibition may be a therapeutic target in these diseases. To address this issue, three specific aims are proposed. Specific Aim 1: Determine the effect of central Rho-kinase inhibition on the regulation of autonomic tone in response to chronic systemic Ang II infusion. These experiments will be carried out in chronically instrumented, conscious New Zealand White rabbits. The Rho-kinase inhibitor, fasudil, will be administered intracerebroventricularly during Ang II infusion, and autonomic tone will be assessed in fasudil- and vehicle-treated rabbits by renal sympathetic nerve activity, baroreflex sensitivity, heart rate variability, changes in heart rate after metoprolol and atropine plasma norepinephrine, and changes in arterial pressure in response to ganglionic blockade. Specific Aim 2: Determine the effects of central Rho-kinase inhibition on the balance between sympatho-excitatory reactive oxygen species (ROS) and sympatho-inhibitory nitric oxide (NO) in sympathetic nuclei in response to systemic Ang II infusion. We will use several methods to quantify oxidative stress and a variety of proteins relevant to ROS and NO bioavailability in autonomic centers of the brainstem and hypothalamus. These studies will be performed on tissue from the rabbits used in Specific Aim 1. Specific Aim 3: Determine if overexpression of RhoA in vitro potentiates Ang II-mediated increases in ROS and decreases in NO bioavailability. In a neuronal cell line, we will evaluate the effects of overexpression of RhoA, the activator of Rho-kinase, on the balance between ROS and NO in response to Ang II stimulation, using the same molecular endpoints as Specific Aim 2. Overall, these studies will provide novel information on a neuronal pathway that could be a therapeutic target in sympathoexcitatory disease states. The didactic component of my training is also described, including journal club, seminar presentations, and courses in advanced physiology, statistics, engineering, and scientific writing. My comprehensive exam will be scheduled for late 2013 or early 2014. I will be supported to attend scientific conferences to present the results of my research. During my Ph.D. training, I will continue to be exposed to clinical medicine by assisting at a free clinic, shadowing UNMC physicians, and attending clinical seminars.

描述（申请人提供）：本申请描述了一项研究计划和研究过程，导致博士学位。学位作为医学博士/ph.D的一部分。内布拉斯加州大学医学中心的计划。研究计划的总体假设是，血管紧张素II（ANG II）激活中枢性旋转激酶，有助于疾病状态的交感神经兴趣（如心力衰竭，高血压），而Rho-kinase抑制可能是这些疾病的治疗靶标。为了解决这个问题，提出了三个具体目标。具体目标1：确定中央Rho-激酶抑制对响应慢性全身ANG II输注的自主性音调调节的影响。这些实验将在长期有意识的新西兰白兔子中进行。 The Rho-kinase inhibitor, fasudil, will be administered intracerebroventricularly during Ang II infusion, and autonomic tone will be assessed in fasudil- and vehicle-treated rabbits by renal sympathetic nerve activity, baroreflex sensitivity, heart rate variability, changes in heart rate after metoprolol and atropine plasma norepinephrine, and changes in arterial pressure in response to神经节封锁。具体目标2：确定中央rho-激酶抑制对响应全身性ANG II输注的交感神经核对交感神经抑制性氧（ROS）（ROS）（ROS）（ROS）（ROS）和交感抑制性一氧化氮（NO）之间的平衡的影响。我们将使用几种方法来量化与ROS相关的氧化应激和各种蛋白质，并且在脑干和下丘脑的自主中心中无生物利用度。这些研究将在特定目标中使用的兔子的组织上进行。特异性目标3：确定RhoA在体外的过表达是否增强了ANG II介导的ROS的增加，而无生物利用度则减少。在神经元细胞系中，我们将使用与特定目标2的分子端点相同的分子端点来评估RhoA（Rho-激酶的激活剂）的过表达对ROS与NO之间的平衡的影响。总体而言，这些研究将提供有关Sympathoex疾病疾病状态的神经元途径的新信息。还描述了我的培训的教学成分，包括期刊俱乐部，研讨会演讲以及高级生理学，统计，工程和科学写作的课程。我的全面考试将于2013年末或2014年初进行。我将受到支持参加科学会议，以介绍我​​的研究结果。在我的博士学位期间培训，我将通过在免费诊所，遮蔽UNMC医生并参加临床研讨会来继续接触临床医学。