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: 9100695
• 负责人: RICHARD E ZIGMOND
• 金额: $ 37.64万
• 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 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9100695
• 关键词: Afferent Neurons; American; Animals; Anus; Atrial Fibrillation; Axotomy; Back; Biochemical; Biological Models; Biological Response Modifiers; CISH gene; Cardiac Death; Cells; Code; Complication; Complications of Diabetes Mellitus; Cytokine Signaling; Defect; Diabetes Mellitus; Diabetic Autonomic Neuropathy; Diabetic Neuropathies; Etiology; Event; Exhibits; Family; Ganglia; Gene Expression; Generations; Genes; Genetic Transcription; Glucose; Growth; Health; Hyperglycemia; IL6ST gene; 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; glycoprotein 130; improved; in vivo; inhibitor/antagonist; injured; mouse model; prevent; receptor; research study; response; role model; sciatic nerve; second messenger; therapy development

DESCRIPTION (provided by applicant): Over 8% of the U.S. population has type 1 or type 2 diabetes and more than twice that are prediabetic. Peripheral 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 hyperglycemia. 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 example, 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 therapy. 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.

描述（由申请人提供）：超过 8% 的美国人口患有 1 型或 2 型糖尿病，其中两倍以上患有糖尿病前期。周围神经病变是“垂死性神经病变”的一个例子，是大多数糖尿病患者中发现的极其严重的并发症。糖尿病自主神经病变 (DAN) 就是其中一种常见疾病，可导致心房颤动、中风和不明原因心源性猝死等多种疾病，因此开发治疗方法势在必行。然而，DAN 的分子基础尚不清楚，但这一知识对于预防和可能逆转这种神经病至关重要。此外，大多数关于糖尿病的动物研究都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，正常的再生如果能够恢复，就可以补偿由高血糖引起的持续轴突变性。现在人们对促进正常动物再生的信号了解很多，但这些进展尚未应用于研究糖尿病的缺陷。我们的实验室研究正常交感神经元对损伤的反应已超过 20 年。通过关注再生相关基因 (RAG) 表达的变化以及调理损伤后生长能力的增加，我们发现这些反应中有许多取决于损伤诱导的 gp130 细胞因子家族炎症细胞因子。这些蛋白质被称为免疫介质，现在也被认为是神经系统内的损伤信号。例如，我们证明了这些细胞因子在基因表达损伤后的特定变化以及正常交感神经元的调节损伤反应中的必然作用。我们建议利用我们在正常动物身上学到的经验教训，在体内和体外糖尿病小鼠模型系统中检查 DAN 的原因和潜在的治疗方法。该提议的中心假设如下：糖尿病的交感神经并发症部分是由于神经元或非神经元细胞中细胞因子诱导的减少和/或受损神经元细胞因子反应性的减少而导致的 gp130 细胞因子信号传导减少所致。这些变化导致 RAG 表达减少、神经突生长减少、再生减少和终末器官功能恢复减少，这些缺陷可能可以通过细胞因子替代疗法逆转。使用这些小鼠模型，我们建议使用神经检查细胞因子表达和交感神经节反应性的调节、已知对神经再生重要的选定基因的表达、再生程度以及内在和外在因素的作用嫁接技术，以及 条件性病变反应的程度。然后我们将确定是否可以通过施用这些细胞因子来改善我们发现的任何缺陷。我们期望这些关于 gp130 细胞因子的研究将有助于阐明糖尿病神经病变的根本原因，并有望带来可以预防、减轻甚至逆转这种严重的糖尿病并发症的治疗方法，例如细胞因子替代疗法。