Gustatory and interoceptive regulation of hypertension

高血压的味觉和内感受调节

• 批准号: 10388488
• 负责人: Caitlin Marie Baumer Harrison
• 金额: $ 3.86万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10388488
• 关键词: Ablation; Acetates; Address; 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; Light; Link; Mediating; Modeling; Mus; Nerve; 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; base; blood pressure reduction; blood pressure regulation; cardiovascular disorder risk; cardiovascular risk factor; experimental study; extracellular; hypertension treatment; hypertensive; in vivo; insight; normotensive; novel; optogenetics; peptide hormone; pressure; receptor; salt sensitive hypertension; sensory integration; sensory system; taste system

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.

项目摘要 钠（NA+）的过度消费是美国和世界各地的主要健康问题， 与许多健康状况有关，包括高血压，这是一个主要风险因素 心血管疾病。虽然Na+-Intake和Hypermension之间的关系广泛 认识到，这种关系背后的机制尚不清楚。提议 实验旨在通过研究来描述这种关系的基础机制 调节Na+taste/intake和血压（BP）的感觉系统。我的初步研究 在小鼠中进行的 血管紧张素1A受体（NPGAT1AR）将传入发送到固体核（NTS）的核。这 NPG包含可作为压力感受器的神经元，可感知血压或味觉 传递na+taste的传入。有趣的是，NTS中传入的光学遗传兴奋 来自NPGAT1AR可显着降低血压和Na+-Intake。而且，老鼠过度耗费 NACL溶液和通过递送乙酸乙酸乙酸根（doca-salt）递送高血压 相对于正常的小鼠，需要更大的刺激频率到较低的血压。 总的来说，我的初步结果表明NPGAT1AR将传入传入到NTS中 血压的拦截和Na+taste的感知和这些神经元的兴奋 可用于研究NA+过度消费后的高血压病因。根据我 已经开发了总体假设，即NPGAT1AR将传入发送给调节血液的NTS 压力和na+ - 智能，以及这些神经元上的AT1AR（S）有助于doca- 盐高血压。为了确认或驳斥这一假设，我将解决以下目标。 AIM 1将使用 NPGAT1AR传入的神经解剖学特征和Ostral中NPGAT1AR传入的光遗传学激活 确定这些传入的连通性和兴奋是否足以 在基本条件下和血容量消耗后，改变Na+ - 感染和血压。 AIM 2将使用CRE-LoxP系统和虚拟介导的基因转移从选择性删除AT1AR NPG确定这些AT1AR是否需要增加Na+-Intake并改进 可容纳高血压DOCA盐模型的BaroreFlex灵敏度。总的来说，这些 实验将阐明脑干中的味觉和感知性整合以更好 了解Na+-Intake和血压调节之间的关系，从而提供新颖 可以利用以开发高血压治疗的洞察力。