Role of Vanilloid Receptors in Diabetic Peripheral Neuropathy

糖尿病周围神经病变（DPN）的特征在于改变的化学、热和机械敏感性。 由于瞬时受体电位（TRP）家族的离子通道转导化学，热和机械 TRP香草素1（TRPV 1）和TRP香草素4（TRPV 4）可能与DPN有关。在本研究中， 我们将使用链脲佐菌素诱导的糖尿病（SD）大鼠作为1型糖尿病（T1 DM）的模型， 糖尿病肥胖（ZDF）大鼠作为2型糖尿病（T2 DM）模型。的表达和功能 将研究伤害感受离子通道TRPV 1和TRPV 4。在初步实验中，使用小鼠模型， 我们发现，糖尿病小鼠表现出热痛觉过敏的初始阶段，随后是热痛觉过敏的阶段。 热痛觉减退这些表型的潜在机制将有助于我们理解超敏反应 以及在糖尿病患者中观察到的明显感觉丧失。在目标1中，我们将确定表达式， TRPV 1和TRPV 4在外周神经末梢和DRG神经元细胞体中的功能。尽管感官 由于神经末梢变性而丧失，有些患者会有烧灼痛的感觉。这表明 外周致敏不是引起疼痛的原因，中枢致敏更有可能参与疼痛的发生。 脊柱和脊柱上部位。在第二个目标中，我们将确定TRPV 1的表达和功能， TRPV 4在脊髓背角的表达，并决定其在突触传递调节中的作用。那就 确定靶向脊髓中的TRP通道是否可以缓解超敏反应。DPN也影响 内脏器官和血管由感觉神经支配，调节传出的非感觉功能。在 第三个目的，我们将确定TRPV 1和TRPV 4在血管中的表达和功能， 通过研究血管张力和内皮细胞功能的变化来评估功能后果。结果 这项研究将增加我们对TRPV 1和TRPV 4的感觉和非感觉功能的理解， 影响疾病进程。糖尿病周围神经病变的并发症可以通过维持正常血糖来预防/延缓 TRP通道的水平和表达以及功能。

Diabetic peripheral neuropathy (DPN) is characterized by altered chemical, thermal and mechanical sensitivities. Since Transient Receptor Potential (TRP) family of ion channels transduces chemical, thermal and mechanical sensation, it is likely that TRP Vanilloid 1 (TRPV1) and TRP Vanilloid 4 (TRPV4) are involved DPN. In this study, we will use streptozotocin-induced diabetic (SD) rats as a model for type1 diabetes mellitus (T1DM) and Zucker diabetic fatty (ZDF) rats as a model for type 2 diabetes mellitus (T2DM). The expression and function of nociceptive ion channels TRPV1 and TRPV4 will be studied. In preliminary experiments, using mouse models of diabetes, we have found that diabetic mice exhibit an initial phase of thermal hyperalgesia followed by a phase of thermal hypoalgesia. The mechanisms underlying these phenotypes will help us understand the hypersensitivity and the marked sensory loss observed in patients with diabetes. In Aim 1, we will determine the expression and function of TRPV1 and TRPV4 in peripheral nerve terminals and the DRG neuronal cell bodies. In spite of sensory loss as a result of nerve terminal degeneration, some patients experience burning pain sensation. This suggests that peripheral sensitization is not responsible for the pain, and central sensitization is more likely to be involved at spinal and supraspinal sites. In the second aim, we will determine the expression and function of TRPV1 and TRPV4 at the spinal dorsal horn and determine their role in the modulation of synaptic transmission. Then, we will determine whether targeting TRP channels in the spinal cord can relieve hypersensitivity. DPN also affects internal organs and blood vessels innervated by sensory nerves mediating efferent nonsensory functions. In the third aim, we will determine the expression and function of TRPV1 and TRPV4 in blood vessels and examine the functional consequence(s) by studying the changes in the vascular tone and endothelial cell functions. Findings from this study will increase our understanding how sensory and nonsensory functions of TRPV1 and TRPV4 impact the disease process. The complications of DPN can be prevented/delayed by maintaining normal glucose levels and expression and function of TRP channels by therapeutic interventions.