gp130 Cytokines, Diabetic Autonomic Neuropathy, and Nerve Regeneration

gp130 细胞因子、糖尿病自主神经病变和神经再生

• 批准号: 8630390
• 负责人: RICHARD E ZIGMOND
• 金额: $ 39.69万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8630390
• 关键词: Afferent Neurons; American; Animals; Anus; Atrial Fibrillation; Axotomy; Back; Biochemical; Biological Models; Biological Response Modifiers; Cardiac Death; Cells; Code; Complication; Complications of Diabetes Mellitus; Cytokine Inducible SH2-Containing Protein; Cytokine Signaling; Defect; Diabetes Mellitus; Diabetic Autonomic Neuropathy; Diabetic Neuropathies; Etiology; Event; Exhibits; Family; Ganglia; Gene Expression; Generations; Genes; Genetic Transcription; Glucose; Glycoproteins; Growth; Hyperglycemia; In Vitro; Inflammatory; Injury; JAK2 gene; Janus kinase; Knowledge; Lead; Learning; Lesion; Measures; Methods; Molecular; Monitor; Motor Neurons; Mus; Natural regeneration; Nerve; Nerve Regeneration; Nervous system structure; Neurites; Neuroglia; Neurons; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Organ; Pancreas; Patients; Peripheral Nerves; Peripheral Nervous System Diseases; Phosphorylation; Physiological; Play; Population; Process; Proteins; Public Health; Recovery; Recovery of Function; Regulation; Replacement Therapy; Reporting; Research Personnel; Rodent Model; Role; STAT protein; Second Messenger Systems; Signal Pathway; Signal Transduction; Signaling Protein; Streptozocin; Stroke; Sympathetic Ganglia; System; Techniques; axonal degeneration; base; conditioning; cytokine; cytokine therapy; design; diabetic; improved; in vivo; inhibitor/antagonist; injured; mouse model; prevent; public health relevance; receptor; research study; response; role model; sciatic nerve; second messenger; therapy development

Over 8% of the U.S. population has type 1 or type 2 diabetes and more than twice that are prediabetic. Pe- ripheral neuropathy, an example of a "dying back neuropathy", is an extremely serious complication found in a majority of diabetics. One such condition, diabetic autonomic neuropathy (DAN), is common and can lead to a wide range of conditions such as atrial fibrillation, stroke, and sudden unexplained cardiac death, making the development of treatments imperative. The molecular basis of DAN, however, is unknown, know- ledge that is vital for preventing and possibly reversing this neuropathy. Furthermore, most animal studies on diabetes have focused on sensory and motor neurons. Diabetic neurons exhibit deficits in nerve regeneration. Many researchers postulate that this is an underlying factor in the etiology of neuropathy and that normal re- generation, if it could be restored, could compensate for on-going axonal degeneration resulting from hypergly- cemia. Much is now known about signals promoting regeneration in normal animals, but these advances have not been applied to studying the deficits in diabetes. Our lab has studied the responses of normal sympathetic neurons to injury for > 20 years. Focusing on changes in regeneration-associated gene (RAG) expression and the increased growth capacity after a conditioning lesion, we discovered that many of these responses depend on injury-induced inflammatory cytokines of the gp130 cytokine family. These proteins, well known as immune mediators, are now also recognized as serving as injury signals within the nervous system. For exam- ple, we demonstrated an obligatory role of these cytokines in specific changes after injury in gene expression and in the conditioning lesion response of normal sympathetic neurons. We propose to use the lessons we have learned in normal animals to examine the cause(s) and potential treatment(s) for DAN in an in vivo and an in vitro mouse model system of diabetes. The central hypothesis of this proposal is as follows: Sympathetic complications of diabetes result in part from decreased gp130 cytokine signaling due to a decrease in cytokine induction in neurons or non-neuronal cells and/or to a decrease in cytokine responsiveness by injured neurons. These changes lead to a decrease in RAG expression, decreased neurite outgrowth, decreased regeneration and decreased recovery of end organ function, deficits that might be reversed by cytokine replacement thera- py. Using these mouse models, we propose to examine the regulation of cytokine expression and responsive- ness in sympathetic ganglia, the expression of selected genes known to be important for nerve regeneration, the extent of regeneration, and the roles of intrinsic and extrinsic factors using nerve grafting techniques, and the extent of the conditioning lesion response. We will then determine if any defects we find can be improved by administering these cytokines. We expect these studies on gp130 cytokines will help to elucidate an under- lying cause for diabetic neuropathy and hopefully lead to treatments--such as cytokine replacement therapy-- that can prevent, lessen, or even reverse this serious complication of diabetes.

超过 8% 的美国人患有 1 型或 2 型糖尿病，其中两倍多处于糖尿病前期。佩- 周围神经病变是“垂死性神经病变”的一个例子，是一种极其严重的并发症 在大多数糖尿病患者中。其中一种病症是糖尿病自主神经病变（DAN），它很常见并且可以 导致多种疾病，如心房颤动、中风和不明原因的心源性猝死， 使得治疗方法的开发势在必行。然而，DAN 的分子基础尚不清楚， 对于预防并可能逆转这种神经病至关重要。此外，大多数动物研究 糖尿病主要集中在感觉和运动神经元上。糖尿病神经元表现出神经再生缺陷。 许多研究人员推测这是神经病病因学的一个潜在因素，并且正常的神经病变 如果可以恢复的话，可以补偿由高血糖引起的持续轴突变性 塞米亚。现在人们对促进正常动物再生的信号了解很多，但这些进展已经 尚未应用于研究糖尿病的缺陷。我们的实验室研究了正常交感神经的反应 神经元损伤超过 20 年。关注再生相关基因（RAG）表达的变化和 条件损伤后生长能力的增加，我们发现其中许多反应取决于 对 gp130 细胞因子家族损伤诱导的炎症细胞因子的影响。这些蛋白质，众所周知 免疫介质，现在也被认为是神经系统内的损伤信号。对于考试—— 因此，我们证明了这些细胞因子在基因表达损伤后的特定变化中的必然作用 以及正常交感神经元的调节损伤反应。我们建议利用我们所学到的经验教训 已经学会在正常动物体内检查 DAN 的原因和潜在的治疗方法 糖尿病的体外小鼠模型系统。该提案的中心假设如下：同情 糖尿病并发症的部分原因是细胞因子减少导致 gp130 细胞因子信号传导减弱 神经元或非神经元细胞的诱导和/或受损神经元细胞因子反应性的降低。 这些变化导致 RAG 表达减少、神经突生长减少、再生减少 以及终末器官功能的恢复下降，这些缺陷可以通过细胞因子替代疗法来逆转 py。使用这些小鼠模型，我们建议检查细胞因子表达的调节和反应- 交感神经节中的神经节，已知对神经再生重要的选定基因的表达， 使用神经移植技术的再生程度以及内在和外在因素的作用，以及 条件性病变反应的程度。然后我们将确定是否可以改进我们发现的任何缺陷 通过施用这些细胞因子。我们预计这些关于 gp130 细胞因子的研究将有助于阐明以下问题： 糖尿病神经病变的潜在原因，并有望导致治疗——例如细胞因子替代疗法—— 可以预防、减轻甚至逆转这种严重的糖尿病并发症。