Neurohumoral regulation of PVAT

PVAT 的神经体液调节

• 批准号: 10331579
• 负责人: BRIAN D. GULBRANSEN
• 金额: $ 33.97万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-22 至 2026-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10331579
• 关键词: Adipocytes; Adipose tissue; Adult; American; Anatomy; Animal Model; Animals; Atherosclerosis; Autocrine Communication; Biological Assay; Blood Pressure; Blood Vessels; Calcium; Cardiovascular Diseases; Cardiovascular system; Catecholamines; Cause of Death; Cells; Complication; Conflict (Psychology); Cues; Data; Disease; Epidemic; Female; Genes; Genetic; Goals; Health; Health Care Costs; Heart failure; High Fat Diet; Human; Hypertension; Image; Impairment; In Vitro; Individual; Label; Lead; Measures; Mediating; Mediator of activation protein; Mesenteric Arteries; Mesentery; Minor; Modeling; Morbidity - disease rate; Mus; Nerve; Neuroglia; Neurotransmitters; Norepinephrine; Obesity; Optics; Pathway interactions; Pharmaceutical Preparations; Play; Preparation; Production; Regulation; Reporter; Role; Signal Transduction; Source; Stroke; Testing; Tetrodotoxin; Thoracic aorta; Tissues; Transgenic Animals; Transgenic Model; Transgenic Organisms; Vascular Diseases; Vasodilation; analog; blood pressure regulation; burden of illness; calcium indicator; cardiovascular disorder risk; cardiovascular risk factor; early onset; experimental study; improved; insight; male; nerve supply; neuroregulation; neurotransmission; neurotransmitter release; neurotransmitter uptake; novel; novel therapeutics; presynaptic; preventable death; relating to nervous system; response; single-cell RNA sequencing; therapy development; transcriptome sequencing; uptake

Project Summary – Project II Cardiovascular disease is the leading cause of death worldwide and encompasses multiple disorders including atherosclerosis, hypertension, stroke, and heart failure. There is a direct positive relationship between blood pressure and cardiovascular disease risk in humans, but the factors that contribute to abnormal blood pressure regulation in disease are incompletely understood. Perivascular adipose tissue (PVAT) has recently emerged as a key regulator of vascular tone and blood pressure. PVAT surrounds the majority of blood vessels and releases anticontractile factors. The production of anticontractile mediators is driven by the sympathetic neurotransmitter norepinephrine (NE), but the source of NE that drives this effect remains unknown. The overall goal of this proposal is to understand the mechanisms that mediate neurotransmission in PVAT in health and disease. Potential mechanisms that drive adipocyte activity include local production of mediators by non-neuronal cells, neural innervation, or circulating neurotransmitters. This proposal tests the central hypothesis that autocrine signaling mediated by the uptake and release of NE by adipocytes is the primary regulator of PVAT adipocyte activity, while neural innervation and circulating factors play minor roles. Further, we propose that the presynaptic functions of PVAT adipocytes are altered in conditions that produce vascular disease. This hypothesis will be tested in two specific aims that will study mesenteric and aortic PVAT in male and female animals during health and disease. Experiments will utilize targeted genetic tracing and tissue clearing to identify physical interactions between nerves and adipocytes, genetically encoded calcium indicators to study adipocyte activation, chemogenetics to test the functional relevance of adipocyte activation, fluorescent false neurotransmitters to study the dynamics of NE uptake and release in adipocytes, and RNA sequencing to understand how specific mechanisms and pathways are regulated during disease. Specific Aim 1 will test the hypothesis that the stimulation of PVAT adipocytes by NE involves autocrine signaling mediated by adipocytes rather direct neural innervation or circulating neurotransmitters. Experiments in this aim include anatomical studies in genetic reporter lines, calcium imaging with genetically encoded indicators, chemogenetics in functional assays of vascular tone, and measures of fluorescent false neurotransmitter uptake and release. Specific Aim 2 will test the hypothesis that presynaptic functions of PVAT adipocytes are impaired in conditions that produce vascular disease. This aim will use the high fat diet model of vascular dysfunction and will study candidate mechanisms with RNA sequencing. Effects on adipocyte neurotransmitter uptake, release, and responsiveness will be studied using fluorescent false neurotransmitters and genetically encoded calcium indicators. The results of this study will identify novel mechanisms that regulate the functions of PVAT. New insight into mechanisms that drive the release of anticontractile factors will facilitate the development of therapies for vascular dysfunction in common disorders, such as hypertension.

项目概要 – 项目 II 心血管疾病是全世界死亡的主要原因，涵盖多种疾病，包括 动脉粥样硬化、高血压、中风和心力衰竭之间有直接的正相关关系。 压力和人类心血管疾病风险，但导致血压异常的因素 最近出现了血管周围脂肪组织（PVAT）的疾病调节机制。 作为血管紧张度和血压的关键调节剂，PVAT 包围着大部分血管。 释放抗收缩因子，抗收缩介质的产生是由交感神经驱动的。 神经递质去甲肾上腺素 (NE)，但驱动这种作用的 NE 来源仍然未知。 该提案的总体目标是了解介导 PVAT 神经传递的机制 驱动脂肪细胞活性的潜在机制包括通过局部产生介质。 该提案测试了中枢神经细胞、神经支配或循环神经递质。 假设脂肪细胞摄取和释放 NE 介导的自分泌信号是主要的 PVAT 脂肪细胞活性的调节剂，而神经神经支配和循环因素则发挥次要作用。 我们提出，PVAT 脂肪细胞的突触前功能在产生血管的条件下发生改变。 该假设将在两个具体目标中进行测试，即研究男性肠系膜和主动脉 PVAT。 实验将利用有针对性的基因追踪和组织。 清除以识别神经和脂肪细胞之间的物理相互作用，基因编码的钙 研究脂肪细胞活化的指标，测试脂肪细胞活化功能相关性的化学遗传学， 荧光假神经递质用于研究脂肪细胞和 RNA 中 NE 摄取和释放的动态 测序以了解疾病期间如何调节特定机制和途径。 1 将检验 NE 对 PVAT 脂肪细胞的刺激涉及自分泌信号介导的假设 通过脂肪细胞而不是直接的神经支配或循环神经递质来实现这一目标的实验包括。 基因报告系的解剖学研究、具有基因编码指标的钙成像、 血管张力功能测定中的化学遗传学以及荧光假神经递质的测量 具体目标 2 将检验 PVAT 脂肪细胞突触前功能的假设。 在产生血管疾病的情况下受损此目标将使用血管的高脂肪饮食模型。 功能障碍，并将通过 RNA 测序研究对脂肪细胞神经递质的影响的候选机制。 将使用荧光假神经递质和基因来研究摄取、释放和反应性 这项研究的结果将确定调节功能的新机制。 对驱动抗收缩因子释放的机制的新见解将促进 开发治疗高血压等常见疾病中血管功能障碍的疗法。