Mechanisms of Type 1 Diabetes in the Autonomic Control of Circulation During Exercise

1 型糖尿病运动期间循环自主控制的机制

基本信息

批准号：
10736121
负责人：
Audrey J Stone
金额：
$ 64.54万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-01 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10736121
关键词：
ASIC channel Affect Attenuated Autonomic Dysfunction Axon Biochemical Blood Pressure Blood flow Cardiovascular Diseases Cardiovascular system Cessation of life Circulation Contracts Dangerousness Data Disease Disease Progression Electrophysiology (science)Event Evolution Exercise Female Functional disorder Goals Health Heart Rate Hindlimb Hyperglycemia Immunohistochemistry Individual Insulin-Dependent Diabetes Mellitus Knock-out Location Measures Mechanics Metabolic Mission Modeling Muscle Muscle Contraction Muscle Fibers Myocardial Infarction Nerve Endings Neurons Outcome Oxygen Pattern Persons Phase Physical activity Population Process Proteins Public Health Rattus Reflex action Research Risk Role Sensory Sex Differences Skeletal Muscle Spinal Ganglia Stroke Techniques Testing Thinness Western Blotting Work arm blood pressure elevation diabetic rat improved in vivo innovation male mortality neural pharmacologic premature receptor response sex

项目摘要

Project Summary/Abstract Although consistent physical activity is routinely prescribed to control hyperglycemia associated with type 1 diabetes (T1D), individual bouts of physical activity may increase the likelihood of evoking dangerous cardiovascular responses (i.e., heart attack and/or stroke). The long-term goal of this project is to elucidate mechanisms of autonomic dysfunction of cardiovascular control dur- ing physical activity to improve health and reduce mortality in those with T1D. The overall objec- tive is to determine the roles of P2X3Rs and ASIC3 on the exaggerated BP response to physical activity in males and females who are differentially afflicted by T1D and cardiovascular disease. The central hypothesis is that the effects of both P2X3Rs and ASIC3 on thin fiber muscle afferents contribute to the exaggerated exercise pressor reflex in T1D rats, an effect that changes with the pathophysiology of the disease. The rationale for this project is that understanding mechanisms of autonomic dysfunction of cardiovascular control, which present in response to physical activity, will lead to treating the temporal pathophysiology of T1D, thereby ameliorating risk of adverse cardiovascular events. The central hypothesis will be tested with three specific aims: 1) Determine the effects of metabolically sensitive P2X3Rs and ASIC3 on the altered exercise pressor reflex in T1D rats at different phases of the disease; 2) Determine the effects of metabolically sensitive P2X3Rs and ASIC3 on group III and IV afferent activity in T1D rats at different phases of the disease; 3) Determine the expression patterns of P2X3Rs and ASIC3 in the DRG neurons of T1D rats at different phases of the disease. For Aim 1, cardiovascular responses to muscle contraction will be measured in T1D rats before and after blocking or stimulating ASIC3 and P2X3Rs. For Aim 2, group III and IV afferent activity during muscle contraction will be measured in T1D rats before and after blocking or stimulating ASIC3 and P2X3Rs. For Aim 3, the location and expres- sion of ASIC3 and P2X3Rs on hindlimb DRG neurons will be determined using various biochem- ical techniques. The research proposed in this application is innovative because this will be the first study to determine the changing interactive effects of receptors and channels evoking reflex- ive blood pressure responses during exercise in both male and female T1D rats. Additionally, this study will be the first to analyze sex differences in blood pressure responses to exercise in T1D. The proposed research is significant because it will provide an initial understanding of possible mechanisms responsible for evoking the exaggerated exercise pressor reflex in T1D.

项目概要/摘要尽管经常进行持续的体力活动来控制相关的高血糖对于 1 型糖尿病 (T1D)，个别的体力活动可能会增加患糖尿病的可能性引起危险的心血管反应（即心脏病发作和/或中风）。长期目标该项目的目的是阐明心血管控制过程中自主神经功能障碍的机制体力活动可改善 1 型糖尿病患者的健康并降低死亡率。总体目标—— 的目的是确定 P2X3R 和 ASIC3 在对物理的夸张 BP 反应中的作用分别患有 T1D 和心血管疾病的男性和女性的活动。中心假设是 P2X3R 和 ASIC3 对细纤维肌肉传入的影响导致 T1D 大鼠过度运动升压反射，这种效应随该疾病的病理生理学。该项目的基本原理是理解机制心血管控制的自主神经功能障碍，这是对体力活动的反应，将导致治疗 T1D 的时间病理生理学，从而改善不良风险心血管事件。中心假设将通过三个具体目标进行检验： 1) 确定代谢敏感的 P2X3R 和 ASIC3 对运动加压反射改变的影响 T1D大鼠处于疾病的不同阶段； 2) 确定代谢敏感的影响 P2X3Rs 和 ASIC3 对 T1D 大鼠不同阶段 III 组和 IV 组传入活动的影响疾病; 3) 确定T1D DRG神经元中P2X3Rs和ASIC3的表达模式处于疾病不同阶段的大鼠。对于目标 1，心血管对肌肉收缩的反应将在阻断或刺激 ASIC3 和 P2X3R 之前和之后在 T1D 大鼠中进行测量。为了目标 2，将测量 T1D 大鼠肌肉收缩期间的第 III 组和第 IV 组传入活动阻断或刺激 ASIC3 和 P2X3R 之前和之后。对于目标 3，位置和表达 ASIC3 和 P2X3Rs 在后肢 DRG 神经元上的作用将使用各种生物化学方法确定技术。本申请中提出的研究具有创新性，因为这将是第一项研究确定了诱发反射的受体和通道的相互作用变化效应雄性和雌性 T1D 大鼠运动期间的血压反应。另外，这这项研究将是第一个分析 1 型糖尿病运动血压反应的性别差异的研究。拟议的研究意义重大，因为它将提供对可能的情况的初步了解引起 T1D 过度运动升压反射的机制。