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

项目总结/摘要 尽管常规规定持续的体力活动以控制与高血糖相关的 对于1型糖尿病（T1 D），单独的体力活动可能会增加 引起危险的心血管反应（即，心脏病发作和/或中风）。远景目标 本课题的主要目的是阐明高血压时心血管自主神经功能紊乱的机制。 加强体力活动，以改善T1 D患者的健康状况并降低死亡率。总体目标-- 目的是确定P2 X3 Rs和ASIC 3在血压对物理刺激的过度反应中的作用。 活动的男性和女性谁是T1 D和心血管疾病的差异折磨。 中心假设是P2 X3 Rs和ASIC 3对细纤维肌传入的作用 有助于T1 D大鼠的过度运动升压反射，这种效应随着时间的推移而变化。 疾病的病理生理学。这个项目的基本原理是， 心血管控制的自主神经功能障碍，这是对身体活动的反应， 将导致治疗T1 D的时间病理生理学，从而改善不良反应的风险。 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P2 X3 Rs和ASIC 3对运动加压反射改变的影响， 在疾病的不同阶段的T1 D大鼠; 2）确定代谢敏感的 P2 X3 Rs和ASIC 3对T1 D大鼠在不同时相的III和IV组传入活动的影响 3）确定T1 D DRG神经元中P2 X3 Rs和ASIC 3的表达模式 在疾病的不同阶段。对于目标1，对肌肉收缩的心血管反应 将在阻断或刺激ASIC 3和P2 X3 R之前和之后在T1 D大鼠中测量。为 目的2：在T1 D大鼠肌肉收缩过程中测量III和IV组传入活动 在阻断或刺激ASIC 3和P2 X3 R之前和之后。对于目标3，位置和表达式- ASIC 3和P2 X3 R在后肢DRG神经元上的锡永将使用各种生物化学方法来确定。 技巧。本申请中提出的研究是创新的，因为这将是 第一项研究，以确定不断变化的相互作用的影响受体和渠道唤起反射- 观察雄性和雌性T1 D大鼠在运动过程中的血压反应。而且这个 这项研究将是第一个分析T1 D患者血压对运动反应的性别差异的研究。 这项拟议中的研究是重要的，因为它将提供一个初步的了解， T1 D中引起过度运动升压反射的机制。

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.