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。在这份协议中，我们将 检查肌肉传入神经元上代谢物敏感受体在以下反应中的作用： 限制后肢肌肉血流后的交感神经活动，如外周动脉闭塞性 由于动脉粥样硬化引起的疾病。将使用股动脉闭塞的大鼠模型来限制后肢血液 流 具体目的1是检测瞬时受体电位香草酸1型（TRPV 1）的表达， 嘌呤能P2 X受体和酸敏感离子通道（ASIC）以及对这些受体激活的反应性 受体。根据我们已发表的工作和为该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了反射交感神经反应， 表达和反应性的背根神经节（DRG）神经元支配肌肉。 具体目的2是研究神经生长因子（NGF）在TRPV 1、P2 X反应中的作用 的ASIC。我们假设DRG神经元中的NGF是神经元异常发展的关键因素。 动脉闭塞后的交感反射反应。我们的试验数据表明， 动脉闭塞大鼠DRG神经元数量增加。我们预计，在肌肉中注入的NGF 使用渗透微型泵的健康大鼠将诱导交感神经对激活 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是研究副产物在TRPV 1，P2 X和ASIC反应中的作用。我们 假设肌肉中积累的代谢物对异常的 股动脉闭塞后交感神经反应。我们预计动脉闭塞会抬高肌肉 与对照相比，副产物如ATP、酸等在更大程度上减少。我们进一步预计， 在健康大鼠的肌肉中慢性输注副产物将增强在大鼠中观察到的反射反应 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.