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New tools for targeting sympathetic neurons that control blood pressure

针对控制血压的交感神经元的新工具

基本信息

批准号：
8613511
负责人：
JOHN P HORN
金额：
$ 17.73万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-15 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8613511
关键词：
Address Anatomy Angiotensin II Arteries Automobile Driving Autonomic ganglion Back Behavior Blood Circulation Blood Pressure Blood Vessels Blood flow Brain Cardiac Cardiovascular Physiology Cardiovascular system Cells Cerebrovascular Circulation Clinical Management Cutaneous Data Development Diabetes Mellitus Electrophysiology (science)Exercise Fast Blue Functional disorder Future G-Protein-Coupled Receptors Ganglia Gene Chips Gene Expression Gene Expression Profile Gene Expression Profiling Genes Genetic Goals Green Fluorescent Proteins Harvest Health Heart Heart failure Hormonal Human Hyperactive behavior Hypertension Ion Channel Kidney Kidney Failure Label Laboratories Limb structure Medical Messenger RNA Methods Molecular Molecular Genetics Motor Mus Muscle Neuraxis Neurons Neuropeptides Obesity Patients Peripheral Phenotype Physiology Play Pressoreceptors Public Health Renal Blood Flow Renin Reporter Role Signal Pathway Site Skin Sorting - Cell Movement Specific qualifier value Striated Muscles Stroke Sympathetic Ganglia Synapses System Testing Tissue-Specific Gene Expression Tracer Transgenic Organisms Vasoconstrictor Agents Vasomotor Walking base blood pressure regulation brain circulation candidate marker cell type data mining gene discovery hypertension control hypertension treatment immunocytochemistry interest neuropeptide Y new therapeutic target novel novel strategies novel therapeutics promoter public health relevance research study tool validation studies vascular bed

项目摘要

DESCRIPTION (provided by applicant): The goal of this exploratory proposal is to discover genes whose expression defines the specialization of vasomotor sympathetic neurons. Such genes represent new tools for manipulating sympathetic neurons and blood pressure control in experimental studies and for developing new therapeutic strategies. The approach will exploit a transgenic reporter mouse in which NPY-promoter sequences drive expression of green fluorescent protein. Messenger RNA will be purified from manually sorted identified neurons, then amplified and analyzed with microarrays to detect gene expression. The proposal is predicated on the novel concept that half of the entire sympathetic outflow of spike activity originates in the ganglia, not the central nervous system, and upon the hypothesis that synaptic amplification in functional subsets of vasomotor sympathetic neurons is tuned to the needs of different vascular beds. Experiments will address one specific aim, which is to discover genes that distinguish vasomotor from non-vasomotor neurons and that identify subsets of sympathetic neurons controlling different aspects of cardiovascular function. Gene expression will be analyzed in four different ganglia that control brain circulation, the heart, the kidney and limb muscle vasculature. The expression analysis will be further refined by using a retrograde tracer to back label neurons that control circulation in muscles, the skin and the kidney and through analysis of gene expression in single cells. Validation studies will employ quantitative PCR, immunocytochemistry and electrophysiology. This project has potential for high-impact. Strong evidence now indicates that hyperactivity in vasomotor postganglionic sympathetic neurons presages 50% of human hypertension and further contributes to problems associated with heart failure and renal failure. These conditions impose a tremendous public health burden, yet existing therapies for clinical management of hypertension remain inadequate. Finding tools for selectively manipulating postganglionic sympathetic activity in cell types that regulate specific vascular beds will advance fundamental scientific and medical understanding of integrated autonomic physiology.

描述（由申请人提供）：该探索性提案的目标是发现其表达定义血管运动交感神经元特化的基因。这些基因代表了在实验研究中操纵交感神经元和血压控制以及开发新治疗策略的新工具。该方法将利用转基因报告小鼠，其中 NPY 启动子序列驱动绿色荧光蛋白的表达。信使 RNA 将从手动分选的已识别神经元中纯化出来，然后进行扩增并用微阵列进行分析以检测基因表达。该提议基于这样一个新概念：整个交感神经尖峰活动流出的一半源自神经节，而不是中枢神经系统，并且基于这样的假设：血管运动交感神经元功能亚群中的突触放大是根据不同血管床的需要进行调整的。实验将解决一个具体目标，即发现区分血管运动神经元和非血管运动神经元的基因，并识别控制心血管功能不同方面的交感神经元亚群。将分析控制大脑循环、心脏、肾脏和四肢肌肉脉管系统的四个不同神经节的基因表达。通过使用逆行示踪剂来反向标记控制肌肉、皮肤和肾脏循环的神经元，并通过分析单细胞中的基因表达，将进一步完善表达分析。验证研究将采用定量 PCR、免疫细胞化学和电生理学。该项目具有产生巨大影响的潜力。现在强有力的证据表明，血管舒缩节后交感神经元的过度活跃预示着 50% 的人类高血压，并进一步导致与心力衰竭和肾衰竭相关的问题。这些情况给公共卫生带来了巨大的负担，但现有的高血压临床治疗方法仍然不足。寻找选择性操纵调节特定血管床的细胞类型中节后交感神经活动的工具将促进对综合自主神经生理学的基本科学和医学理解。