Role of Vanilloid Receptors in Diabetic Peripheral Neuropathy

糖尿病周围神经病变(DPN)的特点是化学、热和机械敏感性改变。 由于瞬时受体电位(Trp)家族离子通道可传递化学、热和机械信号 感觉，可能是色氨酸香草素1(TRPV1)和色氨酸香草素4(TRPV4)参与了DPN。在这项研究中， 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)和Zucker的模型 糖尿病肥胖(ZDF)大鼠作为2型糖尿病(T2 DM)模型。的表达方式和功能 伤害性离子通道TRPV1和TRPV4将被研究。在初步实验中，使用小鼠模型 对于糖尿病，我们发现糖尿病小鼠表现出最初的热痛觉过敏阶段，随后是 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 在糖尿病患者中观察到明显的感觉丧失。在目标1中，我们将确定表达式和 TRPV1和TRPV4在周围神经末梢和背根节神经元胞体中的作用。不管感官上的 由于神经末梢变性而丢失，有些患者会有灼痛感。这表明 外周敏化不是疼痛的原因，中枢敏化更有可能参与疼痛。 脊椎和棘上部位。在第二个目标中，我们将确定TRPV1和TRPV1的表达和功能 TRPV4位于脊髓背角，并确定它们在突触传递调制中的作用。那么，我们会 确定靶向脊髓中的Trp通道是否可以缓解超敏反应。DPN也会影响 由感觉神经支配的内脏和血管，调节传出的无感觉功能。在 第三个目的，我们将测定TRPV1和TRPV4在血管中的表达和功能，并检测 功能结果(S)通过研究血管张力和内皮细胞功能的变化。发现 这项研究将加深我们对TRPV1和TRPV4的感觉和非感觉功能的理解 影响疾病进程。维持正常血糖可预防/延缓DPN的并发症 治疗干预下色氨酸通道的水平、表达和功能。

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.