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The Neural Mechanisms of Hypertension

高血压的神经机制

基本信息

批准号：
8986722
负责人：
Yumei Feng Earley
金额：
$ 36.85万
依托单位：
UNIVERSITY OF NEVADA RENO
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-12-15 至 2019-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8986722
关键词：
Acetates Acute Address Affect Angiotensin II Angiotensinogen Antihypertensive Agents Autopsy Binding Biological Neural Networks Biology Blood Pressure Brain Breeding Cardiovascular Diseases Cardiovascular system Categories Cessation of life Chromatin Complex Data Dependovirus Development Disease Enzymes Epigenetic Process Essential Hypertension Event Generations Goals Health Heart Rate Histones Human Hyperactive behavior Hypertension Hypothalamic structure Inactive Renin Indium Integral Membrane Protein Kidney Knock-in Knock-out Knockout Mice Laboratories Lamina Terminalis LoxP-flanked allele Lysine MAPK3 gene Mediating Microinjections Mitogen-Activated Protein Kinases Modeling Modification Morbidity - disease rate Mouse Strains Mus Mutant Strains Mice Neurofilament-H Neurons Pathogenesis Patient Care Patients Peptides Peptidyl-Dipeptidase A Physiological Play RNA Receptor Activation Receptor Signaling Receptor, Angiotensin, Type 1 Recombinant adeno-associated virus (rAAV)Renin Renin-Angiotensin System Reporting Research Risk Factors Role Sampling Signal Pathway Signal Transduction Sodium Chloride Stimulus Techniques Telemetry Testing United States Up-Regulation Vasopressins blood pressure regulation chromatin immunoprecipitation hormone regulation human subject hypertension treatment insight mortality mouse model neuromechanism new therapeutic target novel novel strategies paraventricular nucleus prevent promoter receptor receptor expression receptor upregulation recombinase response salt sensitive hypertension small hairpin RNA

项目摘要

DESCRIPTION (provided by applicant): Cardiovascular disease (CVD) remains a leading cause of morbidity and mortality despite recent advances in pharmacological therapy and acute patient care. Hypertension is the major risk factor for CVD and contributes to 95% of CVD deaths. Salt-sensitive hypertension (SSH) is a major form of human primary hypertension. Central mechanisms involving the lamina terminalis and the paraventricular nucleus (PVN) of the hypothalamus play an important role in the development of SSH. In particular, the angiotensin II (Ang II) type 1 receptor (AT1R) in the PVN mediates increases in sympathetic tone and blood pressure (BP) in response to high salt. The (pro)renin receptor (PRR) is a newly discovered component of the renin-angiotensin system (RAS). Binding of renin or prorenin to the PRR promotes Ang II formation and also activates Ang II- independent mitogen-activated protein kinase (MAPK) signaling. Our preliminary data show that PRR expression levels are elevated in the PVN of hypertensive human subjects; however, the significance of this elevation during hypertension is not known. Our central hypothesis is that hypertensive stimuli increase PRR expression epigenetically in the PVN, which promotes local Ang II formation through activation of prorenin, leading to sympathoexcitation and hypertension. To test this hypothesis, we will apply PVN microinjection and telemetry recording techniques to a mouse model of experimentally SSH. Central to these studies is a PRR conditional knockout mouse strain (Nefh-PRRKO) that we generated by breeding mice expressing Cre recombinase under the control of a neuron-specific neurofilament-H (Nefh) promoter, produced in our laboratory, with PRR-floxed mice. Our objectives are to delineate the functional importance of PRR signaling pathways in the PVN in hypertension and elucidate the epigenetic mechanisms leading to PRR elevation. The following specific aims will be addressed: 1) Test the hypothesis that PRR activation in the PVN mediates the development of hypertension. 2) Test the hypothesis that mitogen-activated protein kinase signaling downstream of the PRR is mandatory for the development of hypertension. 3) Identify the epigenetic mechanisms responsible for elevated PRR expression in the PVN in hypertension. The proposed research will uncover the role of the PVN PRR in hypertension and elucidate the underlying signaling mechanisms. By establishing the importance of the PRR in hypertension and describing novel therapeutic targets, these studies will have a direct impact on cardiovascular biology and may open the door to the development of a new category of antihypertensive drugs.