Role of Vanilloid Receptors in Diabetic Peripheral Neuropathy

香草酸受体在糖尿病周围神经病变中的作用

• 批准号: 7682748
• 负责人: LOUIS S PREMKUMAR
• 金额: $ 7.28万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7682748
• 关键词: Affect; Afferent Neurons; Agonist; Animals; Area; Blood Vessels; Blood flow; Burning Pain; CALCA gene; Calcitonin Gene-Related Peptide; Cardiovascular system; Cell physiology; Chemicals; Complications of Diabetes Mellitus; Diabetes Mellitus; Diabetic mouse; Disease; Electrophysiology (science); Endothelial Cells; Esthesia; Exhibits; Family; Glucose; Hypersensitivity; Inflammatory; Ion Channel; Mechanics; Mediating; Mesenteric Arteries; Modeling; Nerve; Neurons; Nociception; Non-Insulin-Dependent Diabetes Mellitus; Organ; Pain; Patients; Peripheral; Peripheral Nerves; Peripheral Nervous System Diseases; Phase; Phenotype; Preparation; Process; Rattus; Resiniferatoxin; Reverse Transcriptase Polymerase Chain Reaction; Role; S100A12 gene; Sensory; Site; Skin; Spinal; Spinal Cord; Streptozocin; Synapses; Synaptic Transmission; Techniques; Therapeutic Intervention; Thermal Hyperalgesias; Time; Vanilloid; Western Blotting; afferent nerve; capsaicin receptor; central sensitization; diabetic; diabetic rat; dorsal horn; experience; human S100A12 protein; neuronal cell body; prevent; receptor; research study

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.

糖尿病周围神经病变（DPN）的特点是改变化学，热和机械敏感性。