Central Regulation of Sodium Appetite via Synergistic Action of RAAS-sensitive Neurons

通过 RAAS 敏感神经元的协同作用对钠食欲进行中枢调节

• 批准号: 10294353
• 负责人: Jon Resch
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10294353
• 关键词: Ablation; Advisory Committees; Aldosterone; Angiotensin II; Angiotensin Type 1a Receptor; Award; Brain; CRISPR/Cas technology; Cells; Censuses; Committee Members; Complex; Consumption; Desire for food; Dietary Sodium; Endocrine; Ensure; Expression Profiling; Foundations; Future; Genetic Engineering; Goals; Grant; Heterogeneity; Hypertension; Impairment; Ingestion; Intake; Israel; Lateral; Maps; Medical center; Medicine; Mentors; Methods; Molecular; Molecular Profiling; Motivation; Mus; Neurons; Neurosciences; Neurosecretory Systems; Nucleus solitarius; Population; Public Health; Recommendation; Regulation; Renin-Angiotensin-Aldosterone System; Research; Research Personnel; Research Training; Signal Transduction; Site; Slice; Sodium; Sodium Chloride; Structure; Structure of terminal stria nuclei of preoptic region; Subfornical Organ; System; Technical Expertise; Techniques; Technology; Testing; Training; Work; base; cardiovascular health; career development; design; droplet sequencing; experimental study; genome-wide; health organization; meetings; mind control; molecular marker; motivated behavior; mouse genetics; neural circuit; neurochemistry; neuromechanism; neuroregulation; optogenetics; programs; relating to nervous system; response; single-cell RNA sequencing; transcriptomics

PROJECT SUMMARY The motivation to consume sodium, often referred to as "sodium (or salt) appetite", is a hard-wired neural response to sodium deficiency regulated by the Renin-Angiotensin-Aldosterone System (RAAS). Impaired function of this system results in inappropriate sodium ingestion that can have deleterious effects on cardiovascular health. The studies and career development activities in this K99/R00 proposal are designed to provide the candidate, Dr. Jon Resch, with the training necessary to become an independent investigator with a research program examining the neural control of sodium appetite. Recently two RAAS-sensitive neuronal populations have been shown to regulate sodium appetite: aldosterone-sensing neurons in the nucleus of the solitary tract (NTSHsd11b2 neurons) and a subpopulation of angiotensin II (AngII)-sensing neurons in the subfornical organ (SFO). Importantly, both NTSHsd11b2 neurons and AngII-sensing SFO neurons are necessary for deficiency-induced sodium appetite, and NTSHsd11b2 neurons require concurrent AngII signaling to drive rapid and robust sodium consumption. Furthermore, both RAAS-sensitive populations promote sodium ingestion via projections to the ventral lateral bed nucleus of the stria terminalis (vlBNST). This strongly suggests that the vlBNST is the critical site where neural processing occurs to coordinate sodium appetite. However, the functional complexity and neurochemical heterogeneity of the vlBNST poses a significant challenge to finding and investigating the neurons within it that regulate sodium appetite. In order to elucidate the neural circuits that control sodium appetite, the proposed research will (1) confirm the site of AngII signaling that enables NTSHsd11b2 neurons to drive sodium appetite, (2) decipher the wiring diagram of RAAS- sensitive inputs to the vlBNST, (3) use high-throughput single-cell transcriptomics to generate a "molecular census" of vlBNST neurons, and (4) identify the molecular signature of vlBNST "sodium appetite" neurons. The results of these experiments will form the foundation for many future studies regarding sodium appetite control by the BNST and the downstream circuits through which these neurons produce the motivation to consume sodium. The proposed research and training will be conducted within the Endocrine Division of the Department of Medicine at Beth Israel Deaconess Medical Center, and will ensure the Dr. Resch's successful transition to scientific independence. Dr. Resch will receive training in CRISPR/Cas9-based methods for mouse genetic engineering from his primary mentor, Dr. Bradford Lowell, and in single-cell transcriptomics from his advisory committee members, Drs. Evan Rosen and Linus Tsai. Furthermore, through acquiring the aforementioned technical expertise, coursework, attendance of scientific meetings, and lab management training from his primary mentor during the initial K99 award period, Dr. Resch will cultivate an independent research program studying the neural control of sodium appetite.

项目摘要 消耗钠的动机，通常被称为“钠（或盐）食欲”，是一种硬连接的神经系统。 对由肾素-血管紧张素-醛固酮系统（RAAS）调节的钠缺乏的反应。受损 该系统的功能导致不适当的钠摄入，这可能对 心血管健康本K99/R 00建议书中的研究和职业发展活动旨在 为候选人Jon Resch博士提供成为独立调查员所需的培训， 一项研究计划，检查神经控制钠的食欲。最近两个RAAS敏感神经元 已经证明，群体可以调节钠的食欲： 孤束（NTSHsd 11b 2神经元）和血管紧张素II（AngII）敏感神经元的亚群， 穹窿下器官（SFO）。重要的是，NTSHsd 11b 2神经元和AngII敏感SFO神经元都是必需的， 对于缺乏诱导的钠食欲，NTSHsd 11b 2神经元需要同时的AngII信号来驱动 快速和强劲的钠消耗。此外，两种RAAS敏感人群均促进钠 通过投射到终纹腹外侧床核（vIBNST）的摄取。这强烈 表明vlBNST是神经处理发生以协调钠食欲的关键部位。 然而，vlBNST的功能复杂性和神经化学异质性构成了一个重要的因素。 寻找和研究其中调节钠食欲的神经元是一个挑战。为了阐明 控制钠食欲的神经回路，拟议的研究将（1）确认AngII的位置 信号，使NTSHsd 11b 2神经元驱动钠食欲，（2）破译RAAS的接线图- vIBNST的敏感输入，（3）使用高通量单细胞转录组学产生“分子 vIBNST神经元的“普查”，和（4）鉴定vIBNST“钠食欲”神经元的分子特征。 这些实验的结果将为未来许多关于钠食欲的研究奠定基础 控制由BNST和下游电路通过这些神经元产生的动机， 消耗钠。拟议的研究和培训将在环境署内分泌司内进行。 贝丝以色列女执事医疗中心的医学部，并将确保Resch博士的成功 向科学独立过渡。Resch博士将接受基于CRISPR/Cas9方法的培训， 他的主要导师Bradford Lowell博士的小鼠基因工程，以及单细胞转录组学 来自他的顾问委员会成员埃文罗森博士和莱纳斯蔡。此外，通过收购 上述技术专长，课程作业，科学会议的出席，和实验室管理 在最初的K99奖励期间，Resch博士将接受他的主要导师的培训，培养独立的 研究神经控制钠食欲的研究项目。