Gustatory and interoceptive regulation of hypertension

高血压的味觉和内感受调节

基本信息

批准号：
10608950
负责人：
Caitlin Marie Baumer Harrison
金额：
$ 2.87万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10608950
关键词：
Ablation Acetates Affect Angiotensin II Angiotensin Type 1a Receptor Angiotensins Attenuated Baroreflex Blood Pressure Blood Volume Brain Brain Stem Brain region Cardiovascular Diseases Cardiovascular Physiology Cardiovascular system Cause of Death Consumption Cre lox recombination system DOCA Deoxycorticosterone Desire for food Detection Development Disease Esthesia Etiology Fluid Balance Foundations Frequencies Ganglia Gene Transfer Goals Health Heart Hypertension Impairment Intake Interoception Kidney Knowledge Link Mediating Modeling Mus Nerve Neuroanatomy Neurons Nucleus solitarius Nutrient Peptides Perception Peripheral Physiological Physiological Processes Play Population Positioning Attribute Pressoreceptors Prevention Process Regulation Research Role Scientist Sensory Signal Transduction Sodium Sodium Chloride Stretching Taste Bud Cell Taste Buds Taste Perception Testing Tissues Tongue Toxin Training Viral Work blood pressure reduction blood pressure regulation cardiovascular disorder risk cardiovascular risk factor experimental study extracellular hypertension treatment hypertensive in vivo insight neuronal excitability neurotransmission normotensive novel optogenetics peptide hormone pressure receptor salt sensitive hypertension sensory integration sensory system taste system

项目摘要

PROJECT SUMMARY The overconsumption of sodium (Na+) is a major health problem in the U.S. and around the world, having been linked to many health conditions, including hypertension—a major risk factor for cardiovascular disease. While the relationship between Na+-intake and hypertension is widely recognized, the mechanism(s) behind this relationship are not well understood. The proposed experiments aim to delineate the mechanism(s) underlying this relationship by investigating sensory systems that regulate Na+-taste/intake and blood pressure (BP). My preliminary studies conducted in mice discovered that neurons within the nodose and petrosal ganglion that express the angiotensin type 1a receptor (NPGAT1aR) send afferents to the nucleus of the solitary tract (NTS). The NPG contains neurons that function as baroreceptors that sense blood pressure or as gustatory afferents that transduce Na+-taste. Intriguingly, optogenetic excitation of afferents in the NTS arising from NPGAT1aR significantly reduces blood pressure and Na+-intake. Moreover, mice overconsuming NaCl solutions and rendered hypertensive via deliver of deoxycorticosterone acetate (DOCA-salt) required greater frequencies of stimulation to lower blood pressure relative to normotensive mice. Collectively, my preliminary results suggest that the NPGAT1aR send afferents to the NTS that mediate the interoception of blood pressure and the perception of Na+-taste and the excitability of these neurons can be used to study the etiology of hypertension that follows Na+ overconsumption. Accordingly, I have developed the overall hypothesis that NPGAT1aR send afferents to the NTS that regulate blood pressure and Na+-intake, and that AT1aR(s) on these neurons contribute to the development of DOCA- salt hypertension. To confirm or refute this hypothesis, I will address the following aims. Aim 1 will use neuroanatomical characterizations and optogenetic activation of NPGAT1aR afferents in the rostral and caudal NTS to determine whether the connectivity and excitation of these afferents are sufficient to alter Na+-intake and blood pressure under basal conditions and following depletion of blood volume. Aim 2 will use Cre-LoxP system and virally-mediated gene transfer to selectively delete AT1aR(s) from the NPG to determine whether these AT1aR are necessary for increased Na+-intake and decreased baroreflex sensitivity that accompany the DOCA-salt model of hypertension. Collectively, these experiments will shed light on gustatory and interoceptive integration in the brainstem to better understand the relationship between Na+-intake and blood pressure regulation, thereby providing novel insight that can be leveraged to develop treatments for hypertension.

项目概要钠 (Na+) 的过度消耗是美国和世界各地的一个主要健康问题，与许多健康状况有关，包括高血压——高血压的一个主要危险因素 Na+ 摄入量与高血压之间的关系广泛存在。人们认识到，这种关系背后的机制尚不清楚。实验旨在通过调查来描绘这种关系背后的机制调节 Na+ 味觉/摄入量和血压 (BP) 的感觉系统。在小鼠中进行的研究发现，结节和岩神经节内的神经元表达血管紧张素 1a 型受体 (NPGAT1aR) 将传入信号发送至孤束核 (NTS)。 NPG 含有充当压力感受器的神经元，可感知血压或味觉有趣的是，NTS 中传入神经的光遗传学激发。 NPGAT1aR 显着降低了小鼠的血压和 Na+ 摄入量。氯化钠溶液并通过递送醋酸脱氧皮质酮（DOCA-盐）来引起高血压需要更大频率的刺激来降低血压正常小鼠的血压相对压力。总的来说，我的初步结果表明 NPGAT1aR 向 NTS 发送传入信息，以进行调解血压的内感受和 Na+ 味觉以及这些神经元的兴奋性可用于研究 Na+ 过度消耗后高血压的病因。提出了总体假设：NPGAT1aR 向调节血液的 NTS 发送传入信号压力和 Na+ 摄入量，以及这些神经元上的 AT1aR 有助于 DOCA- 的发展为了证实或反驳这一假设，我将提出以下目标。头侧和侧侧 NPGAT1aR 传入神经的神经解剖学特征和光遗传学激活尾部 NTS 以确定这些传入神经的连接性和兴奋是否足以在基础条件下和血容量耗尽后改变Na + 摄入量和血压。目标 2 将使用 Cre-LoxP 系统和病毒介导的基因转移来选择性地删除来自 NPG 以确定这些 AT1aR 是否是增加 Na+ 摄入量和减少 Na+ 摄入量所必需的伴随高血压 DOCA 盐模型的压力感受反射敏感性。实验将揭示脑干中的味觉和内感受整合，以更好地了解 Na+ 摄入量与血压调节之间的关系，从而提供新的可用于开发高血压治疗方法的见解。