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

基本信息

批准号：
10331894
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
项目类别：
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/10331894
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 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

项目摘要

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.

项目概要消耗钠的动机，通常被称为“钠（或盐）食欲”，是一种硬连线的神经系统。肾素-血管紧张素-醛固酮系统（RAAS）调节对钠缺乏的反应。受损该系统的功能会导致钠摄入不当，从而对身体产生有害影响心血管健康。本 K99/R00 提案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钠食欲的神经控制的研究项目。最近两个RAAS敏感神经元人群已被证明可以调节钠食欲：细胞核中的醛固酮感应神经元孤束（NTSHsd11b2 神经元）和血管紧张素 II (AngII) 感受神经元亚群穹窿下器官（SFO）。重要的是，NTSHsd11b2 神经元和 AngII 感知 SFO 神经元都是必需的对于缺乏引起的钠食欲，NTSHsd11b2 神经元需要并发 AngII 信号传导来驱动快速而强劲的钠消耗。此外，两种 RAAS 敏感人群都会促进钠摄入通过投射到终纹腹侧侧床核（vlBNST）的摄入。这强烈地表明 vlBNST 是神经处理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重要的问题。寻找和研究其中调节钠食欲的神经元是一项挑战。为了阐明控制钠食欲的神经回路，拟议的研究将（1）确认 AngII 的位点使 NTSHsd11b2 神经元驱动钠食欲的信号传导，(2) 破译 RAAS- 的接线图 vlBNST 的敏感输入，(3) 使用高通量单细胞转录组学生成“分子 vlBNST 神经元的普查”，(4) 识别 vlBNST“钠食欲”神经元的分子特征。这些实验的结果将为未来许多有关钠食欲的研究奠定基础由 BNST 和下游电路控制，这些神经元通过这些电路产生动机消耗钠。拟议的研究和培训将在内分泌科进行贝斯以色列女执事医疗中心医学部，将确保 Resch 博士的成功向科学独立的过渡。 Resch 博士将接受基于 CRISPR/Cas9 方法的培训他的主要导师 Bradford Lowell 博士教授小鼠基因工程和单细胞转录组学来自他的顾问委员会成员，博士。埃文·罗森和莱纳斯·蔡。此外，通过收购上述技术专长、课程作业、参加科学会议和实验室管理在最初的 K99 奖励期间，Resch 博士将在他的主要导师的指导下培养独立的研究钠食欲的神经控制的研究项目。