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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

基本信息

批准号：
8529697
负责人：
RICHARD E ZIGMOND
金额：
$ 15.7万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-21 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8529697
关键词：
Animals Atrial Fibrillation Axotomy Back Biochemical Biological Models Biological Response Modifiers Cardiac Death Cells Code Complication Complications of Diabetes Mellitus Cytokine Signaling Defect Diabetes Mellitus Diabetic Autonomic Neuropathy Diabetic Neuropathies Etiology Event Exhibits Family Gene Expression Genes Genetic Transcription Glucose Growth Hyperglycemia In Vitro Inflammatory Injury Knowledge Laboratories Lead Learning Lesion Measures Methods Molecular Monitor Mus Natural regeneration Nerve Nerve Regeneration Nervous system structure Neurites Neuroglia Neurons Neuropathy Non-Insulin-Dependent Diabetes Mellitus Organ Patients Peripheral Peripheral Nerves Phosphorylation Physiological Play Population Process Protein Family Proteins Public Health Recovery Recovery of Function Regulation Replacement Therapy Research Personnel Rodent Model Role Second Messenger Systems Signal Pathway Signal Transduction Signaling Protein Stat3 protein Streptozocin Stroke Sweat Glands Sympathetic Ganglia System axonal degeneration base conditioning cytokine cytokine therapy design diabetic improved improved functioning in vivo injured mouse model nerve supply prevent receptor research study response role model sciatic nerve second messenger therapy development transcription factor

项目摘要

Approximately 8% of the U.S. population has type 1 or type 2 diabetes and twice that are prediabetic. Periph- eral 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 very 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, knowl- edge that is vital for preventing, and possibly reversing, this neuropathy. Diabetic neurons exhibit deficits in nerve regeneration. Many researchers postulate that this is an underlying factor in the etiology of neuropathy and that normal regeneration, if it could be restored, could compensate for on-going axonal degeneration re- sulting 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 laboratory has studied the re- sponses of normal sympathetic neurons to injury for the past twenty years. Focusing on changes in regenera- tion-associated gene expression and the increased growth capacity after injury, we discovered that most of these responses depend on injury-induced inflammatory cytokines of the gp130 cytokine family. These proteins, well known as immune mediators, are becoming increasingly recognized as serving also as injury signals within the nervous system. For example, we demonstrated an obligatory role of these cytokines in spe- cific changes in gene expression and in the intrinsic growth capacity of normal sympathetic neurons after in- jury. We propose to adapt the methods we have used and 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 non-neuronal cells and/or a decrease in cytokine responsiveness by injured neurons. These changes lead to a decrease in rege- neration-associated gene 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 responsiveness, the ability of a conditioning lesion to increase the growth capacity of sympathetic neurons, and the expression of selected genes known to be important for nerve regeneration, and we will determine if any defects can be improved by administering cytokines. In addition, we will use the sympathetic innervation of sweat glands to look at regen- eration in vivo and return of autonomic function in diabetes. We expect these studies on gp130 cytokines will help to elucidate an underlying cause for diabetic neuropathy and hopefully lead to treatments--such as cyto- kine replacement therapy--that can prevent, lessen, or even reverse this serious complication of diabetes.

大约8%的美国人口患有1型或2型糖尿病，其中2倍为糖尿病前期。周- 神经性神经病是“垂死的背部神经病”的一个例子，是一种在神经系统疾病中发现的极其严重的并发症。大多数糖尿病患者。糖尿病自主神经病变（DAN）是一种非常常见的疾病，导致多种疾病，如心房纤颤、中风和原因不明的心源性猝死，使得治疗的发展势在必行。然而，DAN的分子基础是未知的，已知的- 边缘，这是至关重要的预防，并可能逆转，这种神经病变。糖尿病神经元表现出神经再生许多研究者假定这是神经病病因学的一个潜在因素正常的再生，如果可以恢复，可以补偿正在进行的轴突变性，由高血糖症引起的现在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。我们的实验室已经研究了- 在过去的二十年中，正常交感神经元对损伤的反应。关注再生能源的变化- 与损伤相关的基因表达和损伤后生长能力的增加，我们发现大多数这些应答依赖于损伤诱导的GP 130细胞因子家族的炎性细胞因子。这些蛋白质，众所周知的免疫介质，越来越多地被认为也是损伤神经系统内的信号。例如，我们证明了这些细胞因子在spe中的强制性作用。在正常交感神经元的基因表达和内在生长能力的cific变化后，陪审团我们建议调整我们使用的方法和我们在正常动物身上学到的教训，在DAN的体内和体外小鼠模型系统中检查DAN的原因和潜在治疗方法，糖尿病该建议的中心假设如下：糖尿病的交感神经并发症导致部分来自由于非神经元细胞中细胞因子诱导的减少而导致的gp 130细胞因子信号传导的减少和/或受损神经元的细胞因子反应性降低。这些变化会导致一个区域的缩小，神经再生相关基因表达减少，神经突生长减少，再生减少，终末器官功能的恢复，可以通过细胞因子替代疗法逆转的缺陷。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，一种条件性损伤，以增加交感神经元的生长能力，以及所选的已知对神经再生很重要的基因，我们将确定是否可以通过以下方式改善任何缺陷给予细胞因子。此外，我们将使用汗腺的交感神经支配来观察再生- 糖尿病患者体内的氧自由基释放和自主神经功能的恢复。我们希望这些对gp 130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，并有望导致治疗--如细胞- 肾脏替代疗法--可以预防，减轻，甚至逆转糖尿病的严重并发症。