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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：
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
项目类别：
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

项目摘要

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，是糖尿病前期的两倍多。Pe -