Sympathetic Nerve Responsiveness and Pri Afferent Neurons with Femorail Artery Oc

动脉粥样硬化是美国发病率和死亡率的主要原因。在这笔赠款中，我们将 探讨代谢物敏感受体在肌肉传入神经元反应中的作用 限制后肢肌肉血流后的交感神经活动，如外周动脉闭塞所见 动脉粥样硬化引起的疾病。大鼠股动脉闭塞模型将用于限制后肢血液 流。 特异性目的1是检测瞬时受体电位香草型1(TRPV1)的表达， 嘌呤能P2X受体和酸敏离子通道及其激活的反应性 感受器。根据我们已发表的工作和为这项提案收集的试点数据，我们假设 股动脉闭塞由于这些受体的增加而增强反射交感反应 支配肌肉的背根节(DRG)神经元的表达和反应性。 具体目的2是研究神经生长因子(NGF)在TRPV1、P2X反应中的作用 和ASIC。我们推测，背根神经节神经元中的神经生长因子是神经节细胞异常发生的关键因素。 动脉闭塞后的反射交感反应。我们的试点数据显示，NGF的水平是 动脉闭塞大鼠背根神经节神经元数量增加。我们预计神经生长因子注入的肌肉中 使用渗透性微泵的健康大鼠将诱导对激活的交感反应增加 这些受体或肌肉收缩；中和NGF将改善交感神经反射 股动脉闭塞大鼠的反应。 具体目标3是检查副产物在TRPV1、P2X和ASICs反应中的作用。我们 假设肌肉中积累的代谢物对异常有重要贡献 股动脉闭塞后的交感反应。我们预计动脉闭塞会使肌肉升高。 与对照相比，副产物如三磷酸腺苷、酸等的程度更高。我们进一步预期， 在健康大鼠的肌肉中长期注入副产物将增强大鼠的反射反应 通过各自的受体进行动脉闭塞。最后，我们预计减弱这些受体将 改善交感神经反应。

Atherosclerosis is the leading cause of morbidity and mortality in the US. In this grant, we will examine the role of metabolite sensitive receptors on muscle afferent neurons in the responses of sympathetic nerve activity after limiting blood flow to hindlimb muscle, as seen in peripheral arterial occlusive disease due to atherosclerosis. A rat model of femoral artery occlusion will be used to restrict hindlimb blood flow. The specific aim 1 is to examine expression of transient receptor potential vanilloid type 1 (TRPV1), purinergic P2X receptors, and acid sensing ion channels (ASICs) and responsiveness to activation of those receptors. Based on our published work and pilot data collected for this proposal, we hypothesize that femoral artery occlusion augments the reflex sympathetic response due to increases in those receptors' expression and responsiveness in dorsal root ganglion (DRG) neurons innervating muscles. The specific aim 2 is to examine the role of nerve growth factor (NGF) in responses of TRPV1, P2X and ASICs. We hypothesize that NGF in the DRG neurons is a key factor for development of abnormality in reflex sympathetic response after artery occlusion. Our pilot data have shown that levels of NGF are increased in DRG neurons of rats with artery occlusion. We anticipate that NGF infused in the muscle of healthy rats using an osmotic minipump will induce an increase in sympathetic response to activation of those receptors or muscle contraction; and neutralization of NGF will improve the reflex sympathetic response in rats with femoral artery occlusion. The specific aim 3 is to examine the role of by-products in responses of TRPV1, P2X and ASICs. We hypothesize that accumulated metabolites in the muscle have an important contribution to abnormal sympathetic response after femoral artery occlusion. We anticipate that artery occlusion will elevate muscle by-products such as ATP, acid, etc. to a greater degree as compared with control. We further anticipate that chronic infusion of by-products in the muscle of healthy rats will augment the reflex responses as seen in rats with arterial occlusion via respective receptors. Finally, we anticipate that attenuating those receptors will improve the sympathetic responses.