Gustatory and interoceptive regulation of hypertension

高血压的味觉和内感受调节

• 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
• 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

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.

项目总结 过量摄入钠(Na+)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--高血压是 心血管疾病。而钠离子摄入量与高血压的关系是广泛的 认识到，这种关系背后的机制(S)并不是很清楚。建议数 实验旨在通过调查来描绘这种关系背后的机制(S) 调节Na+-味觉/摄入量和血压的感觉系统。我的初步研究 在小鼠身上进行的研究发现，结状神经节和岩神经节中表达 血管紧张素1a型受体(NPGAT1aR)向孤束核(NTS)传递传入神经。这个 NPG中的神经元起压力感受器的作用，感知血压或味觉 转导Na+-味觉的传入。耐人寻味的是，NTS中传入神经的光基因兴奋 来自NPGAT1aR显著降低血压和钠摄入量。此外，老鼠过度消费 氯化钠溶液和醋酸脱氧皮质酮(DOCA-SALT)递送致高血压 与正常血压的小鼠相比，需要更高的刺激频率来降低血压。 总而言之，我的初步结果表明，NPGAT1aR向NTS发送传入信息， 血压的内感、钠味觉和这些神经元的兴奋性 可用于研究Na+过量摄入所致高血压的病因。因此，我 已经提出了NPGAT1aR向调节血液的NTS发送传入信号的总体假设 压力和Na+摄取，以及这些神经元上的AT1aR(S)参与了DOCA的发生。 盐分高血压。为了证实或驳斥这一假设，我将阐述以下目标。AIM 1将使用 吻侧和下丘脑NPGAT1aR传入的神经解剖学特征和光发生激活 以确定这些传入神经的连接性和兴奋性是否足以 改变基础状态下和耗尽血容量后的Na+摄入量和血压。 目的利用Cre-loxP系统和病毒介导的基因转移技术选择性缺失AT1aR(S) NPG以确定这些AT1aR是否是增加和减少Na+摄取所必需的 压力感受性反射敏感性伴随DOCA-SALT高血压模型。总而言之，这些 实验将阐明脑干中味觉和内感的整合，以更好地 了解钠离子摄入量与血压调节的关系，从而提供新的 可以利用的洞察力来开发高血压的治疗方法。