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％的美国人口患有1型或2型糖尿病，糖尿病前期是两倍以上。 pe Ripheral Neuropathy是“垂死的神经病”的一个例子，是一个非常严重的并发症 在大多数糖尿病患者中。一种这样的疾病，糖尿病自主神经病（DAN）很常见，可以 导致多种疾病，例如房颤，中风和突然无法解释的心脏死亡， 使治疗的发展必须进行。然而，DAN的分子基础是未知的，知识 - 壁架对于预防和可能逆转这种神经病至关重要。此外，大多数动物研究 糖尿病专注于感觉和运动神经元。糖尿病神经元在神经再生中表现出缺陷。 许多研究人员认为，这是神经病变病因的根本因素，正常情况下 如果可以恢复的话，可以补偿因超gly-导致持续的轴突变性 塞米亚。现在，关于促进普通动物再生的信号已经知道了很多，但是这些进展已有 不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 神经元受伤> 20年。专注于再生相关基因（RAG）表达和 调节病变后的生长能力提高，我们发现其中许多反应取决于 在损伤引起的GP130细胞因子家族的炎症细胞因子上。这些蛋白质，称为 免疫介质现在也被认为是神经系统中的损伤信号。进行考试 ple，我们证明了这些细胞因子在基因表达损伤后特定变化中的强制性作用 在正常交感神经元的调节病变反应中。我们建议使用我们的课程 已经在普通动物中学到了DAN在体内和 糖尿病的体外小鼠模型系统。该提议的中心假设如下：同情 糖尿病的并发症由于细胞因子的降低而导致的GP130细胞因子信号降低导致部分原因 神经元或非神经元细胞的诱导和/或受伤神经元细胞因子反应的降低。 这些变化导致抹布表达降低，神经突产突的降低，再生降低 并降低了最终器官功能的恢复，可能会因细胞因子置换而逆转的缺陷 - py。使用这些小鼠模型，我们建议检查细胞因子表达和反应性的调节 在交感神经中的ness，所选基因的表达对神经再生很重要， 使用神经嫁接技术的再生程度以及内在和外在因素的作用，以及 调节病变反应的程度。然后，我们将确定是否可以改善我们发现的任何缺陷 通过施用这些细胞因子。我们希望这些对GP130细胞因子的研究将有助于阐明不足 撒谎引起糖尿病神经病的原因，并希望导致疗法 - 例如细胞因子替代疗法 - 这可以防止，减少甚至扭转这种严重的糖尿病并发症。