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，糖尿病前期是两倍以上。周围神经病变是“死亡后卫神经病”的一个例子，是大多数糖尿病患者中非常严重的并发症。一种这样的疾病，即糖尿病自主神经病（DAN），很常见，可能导致多种疾病，例如心房颤动，中风和突然无法解释的心脏死亡，这使得治疗的发展必要。但是，DAN的分子基础是未知的，对于预防和可能逆转这种神经病至关重要的知识。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，如果可以恢复正常产生，则可以弥补因高血糖而导致的持续轴突变性。现在已经了解了促进正常动物再生的信号，但是这些进步尚未用于研究糖尿病缺陷。我们的实验室研究了正常的交感神经元对损伤的反应超过20年。重点关注与再生相关基因（RAG）表达的变化和调节病变后的生长能力的增加，我们发现其中许多反应取决于损伤诱导的GP130细胞因子家族的炎症细胞因子。这些蛋白质（众所周知的免疫介质）现在也被认为是神经系统中的损伤信号。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病变反应中的强制性作用。我们建议使用我们在普通动物中学到的教训来检查DAN在体内和糖尿病体外小鼠模型系统中的原因和潜在治疗方法。该提案的中心假设如下：糖尿病的交感神经并发症部分导致了由于神经元或非神经元细胞的细胞因子诱导降低和/或受伤神经元的细胞因子诱导降低而导致的GP130细胞因子信号传导降低。这些变化会导致抹布表达降低，神经突产物的降低，再生减少和终端器官功能的恢复降低，可能会因细胞因子替代疗法而逆转的缺陷。使用这些小鼠模型，我们建议检查交感神经节中细胞因子表达和反应的调节，所知基因的表达对于神经再生，再生的程度以及使用神经疗法的内在和外在因素的作用，以及神经移植技术，以及神经移植技术，以及 调节病变反应的程度。然后，我们将通过施用这些细胞因子来确定是否可以改善我们发现的任何缺陷。我们预计这些对GP130细胞因子的研究将有助于阐明糖尿病神经病的不足原因，并希望导致治疗 - 例如细胞因子替代疗法，可以预防，减少甚至逆转这种严重的糖尿病并发症。