Novel role of central AT2R in blood pressure regulation

中枢 AT2R 在血压调节中的新作用

• 批准号: 8805192
• 负责人: Annette Diane de Kloet
• 金额: $ 11.23万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8805192
• 关键词: Accounting; Address; Adult; Agonist; Angiotensin II; Angiotensins; Animals; Antihypertensive Agents; Autonomic nervous system; Blood Pressure; Body Weight; Brain; Brain Stem; Brain region; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Categories; Cause of Death; Cells; Competence; Complement; Core Facility; Development; Drug resistance; Electrophysiology (science); Environment; Faculty; Florida; Genetic; Genetic Recombination; Goals; Health; Hypertension; Hypothalamic structure; Impairment; In Situ Hybridization; In Vitro; Laboratories; Lead; Learning; Mentors; Mus; National Research Service Awards; Nerve; Neurons; Neurosecretory Systems; Neurotransmitters; Pathway interactions; Patients; Peptides; Pharmaceutical Preparations; Phase; Physiology; Population; Positioning Attribute; Postdoctoral Fellow; Process; Property; Public Health; Receptor Activation; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Research; Resistant Hypertension; Risk Factors; Rodent; Role; Scientist; Site; Stimulus; Structure; Sympathetic Nervous System; Synapses; System; Techniques; Testing; Therapeutic; Therapeutic Uses; Training; Type 2 Angiotensin II Receptor; Universities; abstracting; blood pressure regulation; career; clinically relevant; design; expectation; falls; gamma-Aminobutyric Acid; glucose metabolism; interest; member; neural circuit; neurogenic hypertension; neuroregulation; neurotransmission; new therapeutic target; novel; paraventricular nucleus; patch clamp; post-doctoral training; prevent; programs; public health relevance; receptor; relating to nervous system; research study; skills; therapeutic development

DESCRIPTION (provided by applicant): Project Summary/Abstract Hypertension is a widespread health problem and a major risk factor for cardiovascular disease, the leading cause of death in the USA. Of particular concern is drug-resistant hypertension, which is accompanied by enhanced sympathetic nervous system activity, indicating that the increased blood pressure arises from neurogenic origins. Nearly one-third of hypertensive patients fall into this category for which there are no effective medications and determining strategies to treat or prevent neurogenic hypertension has great significance for public health. My overall career goal is to become an independent academic scientist that studies impairments in neural circuits that elicit neurogenic hypertension, as well as the development of therapeutics that alleviate these impairments. The expectation is that my research will contribute substantively to the understanding of the causes of neurogenic hypertension and to the development of therapeutics used to treat it. The activities proposed in this application are designed to facilitate reaching tis goal and will investigate a novel therapeutic target for neurogenic hypertension - angiotensin type-2 receptors (AT2R) expressed within the brain. The experiments test the overall hypothesis that activation of AT2R on neurons that project to the paraventricular nucleus of the hypothalamus (PVN; a brain region important for controlling sympathetic outflow and blood pressure) negatively-regulate blood pressure, potentially making activation of AT2R a suitable target for antihypertensive medications. My graduate training used laboratory rodents to examine how angiotensin-II, a peptide heavily implicated in the development of hypertension and cardiovascular disease, influenced the neural control of body weight and glucose metabolism. This line of research introduced me to the central pathways that were sensitive to angiotensin-II, which piqued my interest in neurogenic hypertension. Consequently, I chose the laboratory of Dr. Colin Sumners at the University of Florida to conduct my postdoctoral training. Dr. Sumners is a leading expert in the field of neurogenic hypertension and his laboratory is part of the Hypertension Center at UF, which is comprised of core facilities and nearly 50 faculty members dedicated to studying high blood pressure. This training environment contributed to my successful post-doctoral NRSA proposal that afforded competence with the assessment of cardiovascular function in rodents, and perhaps more importantly, found that experimentally-induced hypertension elicited changes within the electrophysiological properties of neurons controlling blood pressure that ultimately increased their excitation. Taking these results into account, I determined that effective therapeutics should decrease or reverse this increased excitation; however, I also determined that additional training in conceptual and technical approaches aimed at understanding the electrophysiological properties of neurons was imperative to developing this line of research. Accordingly, the primary objectives of the K99-phase are to answer some fundamental questions regarding the structure and function of specific AT2R that are positioned to decrease sympathetic outflow and blood pressure, while providing additional training for in vitro patch-clamp electrophysiology. It is anticipated that determining the therapeutic utility of AT2R for neurogenic hypertension and expertise in subcellular neural electrophysiology can be complemented by professional development activities to launch my independent research career. In the first Aim, experiments will combine genetic and neuroanatomical techniques to test the specific hypothesis that AT2R-expressing neurons that make contacts onto preautonomic neurons within the paraventricular nucleus of the hypothalamus express the inhibitory neurotransmitter (GABA), thereby positioning them to decrease blood pressure and autonomic function. In Aim 2, experiments will use patch- clamp electrophysiological techniques to test the specific hypothesis that activation of AT2R on GABA neurons that project to the PVN will facilitate inhibitory (i.e., GABAergic) neurotransmission and that this will lead to reduced activity of PVN preautonomic neurons. These experiments will not only determine precisely how activation of AT2R impact activity within a neuronal network, but they will also serve as a training vehicle for me to learn patch-clamp electrophysiology, a technique that is essential to understanding how subcellular changes in a discrete population of neurons can impact whole animal physiology. Importantly, my background, combined with expertise in electrophysiology will make my research program unique, as it will allow for the study of precisely how angiotensin-II acting through AT2R influences the excitability of specific neurons that control cardiovascular function. Aim 3 will be contained within the R00-phase and will partner my past training with my newly-acquired skills to determine the role of AT2R in blood pressure regulation basally and during neurogenic hypertension. Using the Cre/lox system and pharmacological approaches, I will selectively activate or inhibit AT2R on neurons that project to the PVN and test the specific hypothesis that these AT2R negatively regulate blood pressure and sympathetic nervous system outflow. Collectively, the proposed studies are significant because they may uncover a novel therapeutic target for treatment of neurogenic hypertension while preparing me to establish an independent research program that addresses a problem with high

描述（由申请人提供）：项目摘要/抽象高血压是普遍存在的健康问题，也是心血管疾病的主要危险因素，这是美国的主要死亡原因。特别关注的是耐药性高血压，伴随着增强的交感神经系统活性，表明血压升高来自神经源性的起源。近三分之一的高血压患者属于没有有效的药物，并且决定治疗或预防神经源性高血压的策略对公共卫生具有重要意义。我的整体职业目标是成为一名独立的学术科学家，研究引起神经源性高血压的神经回路的损害以及减轻这些障碍的治疗剂的发展。期望我的研究将有助于理解神经源性高血压的原因以及用于治疗它的治疗剂的发展。本应用中提出的活动旨在促进达到目标的目标，并将研究用于神经源性高血压 - 血管紧张素2受体（AT2R）的新型治疗靶标。该实验检验了总体假设，即AT2R激活在下丘脑的旁脑核（PVN;大脑区域都对控制交感神经流出和血压）的重要调节的神经元上的神经元激活，这可能会对血压进行负调控，并有可能使AT2R激活成为合适的目标。用于降压药。我的研究生培训使用实验室啮齿动物来检查血管紧张素II是一种与高血压和心血管疾病发展有关的肽如何影响体重和葡萄糖代谢的神经控制。这项研究线向我介绍了对血管紧张素II敏感的中心途径，这激发了我对神经源性高血压的兴趣。因此，我选择了佛罗里达大学的科林·史克斯（Colin Sumners）博士的实验室来进行博士后培训。 Sumners博士是神经源性高血压领域的领先专家，他的实验室是UF高血压中心的一部分，UF由核心设施和近50位专门研究高血压的教职员工组成。这个训练环境有助于我成功的博士后NRSA提案，该提案具有评估啮齿动物中心血管功能的能力，也许更重要的是发现，实验诱导的高血压高血压在控制血压的电生理特性中最终提高了其最终增加的高血压变化励磁。考虑到这些结果，我确定有效的治疗剂应减少或扭转这种增加的激发。但是，我还确定了旨在理解神经元电生理特性的概念和技术方法的其他培训对于开发这一研究趋势至关重要。因此，K99期的主要目标是回答有关特定AT2R的结构和功能的一些基本问题，这些问题可降低交感神经流出和血压，同时为体外斑块钳电生理学提供额外的培训。可以预料，确定AT2R的治疗效用用于神经源性高血压和亚细胞神经电生理学方面的专业知识，可以通过专业发展活动来补充，以启动我的独立研究职业。在第一个目标中，实验将结合遗传和神经解剖技术，以检验以下特定假设：AT2R表达神经元在下丘脑旁脊髓核内接触的神经元与抑制性神经脱蛋白的核神经元内的抑制作用（GABA），从而降低了血迹​​，从而降低了血迹和自主功能。在AIM 2中，实验将使用斑块夹电生理技术来测试特定假设，即向PVN投射的GABA神经元上的AT2R激活将促进抑制性（即GABA能）神经传递，并且这将导致PVN PREAUTONOMIC神经元活动降低。这些实验不仅将确切地确定AT2R在神经元网络中的激活如何激活，而且它们还将作为我学习斑块夹电生理学的训练工具，这是一种对了解离散人群中亚细胞变化至关重要的技术神经元可能会影响整个动物生理学。重要的是，我的背景与电生理学专业知识相结合将使我的研究计划与众不同，因为它将允许精确研究血管紧张素II通过AT2R作用如何影响控制心血管功能的特定神经元的兴奋性。 AIM 3将包含在R00期间，并将与我过去的训练与新的培训相结合，以确定AT2R在基本和神经发生高血压过程中的血压调节中的作用。使用CRE/LOX系统和药理学方法，我将选择性地激活或抑制向PVN投射的神经元的AT2R，并检验这些AT2R负调节血压和交感神经系统流出的具体假设。总的来说，拟议的研究很重要，因为它们可能会发现一种新型的治疗神经源性高血压治疗的治疗靶点