gp130 Cytokines, Diabetic Autonomic Neuropathy, and Nerve Regeneration

超过8%的美国人患有1型或2型糖尿病，糖尿病前期患者的比例是前者的两倍以上。体育-- 周围神经病是一种非常严重的并发症，是一种“垂死性背神经病”。 在大多数糖尿病患者中。其中一种情况是糖尿病自主神经病变(DAN)，它很常见，而且可以 导致房颤、中风和不明原因的心源性猝死等多种疾病， 这使得治疗方法的发展势在必行。然而，丹的分子基础是未知的，知道吗- 这对于预防和可能逆转这种神经病变至关重要。此外，大多数动物研究都是关于 糖尿病主要集中在感觉神经元和运动神经元。糖尿病神经元在神经再生方面表现出缺陷。 许多研究人员假设，这是神经病的病因中的一个潜在因素，而正常的反应。 这一代，如果它可以恢复的话，可以弥补由于高血糖引起的正在进行的轴突退化- 克米亚。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 没有被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 神经元对损伤的反应时间为20年。关注再生相关基因(RAG)表达的变化和 在条件性损伤后生长能力的增加，我们发现这些反应中的许多依赖于 关于gp130细胞因子家族中损伤诱导的炎性细胞因子。这些蛋白质众所周知地被称为 免疫介质，现在也被认为是神经系统内的损伤信号。为了考试- 我们证明了这些细胞因子在损伤后基因表达的特定变化中所起的强制性作用。 在正常交感神经元的条件性损伤反应中。我们建议利用我们所学到的经验 已学会在正常动物体内研究丹的病因(S)和潜在的治疗方法(S)。 糖尿病小鼠体外模型系统的建立。这一提议的中心假设如下：同情 糖尿病并发症的部分原因是由于细胞因子的减少导致gp130细胞因子信号的减少。 神经元或非神经元细胞的诱导和/或受损神经元细胞因子反应性的降低。 这些变化导致RAG表达减少，轴突生长减少，再生减少 减少终末器官功能的恢复，这些缺陷可能会被细胞因子替代疗法逆转- Py.利用这些小鼠模型，我们建议研究细胞因子表达和反应的调节。 交感神经节中的Ness，已知对神经再生重要的选定基因的表达， 使用神经移植技术再生的程度，以及内在和外在因素的作用，以及 条件性损伤反应的程度。然后，我们将确定我们发现的任何缺陷是否可以改进 通过使用这些细胞因子。我们期望这些关于gp130细胞因子的研究将有助于阐明 糖尿病神经病变的诱因，并有望导致治疗--如细胞因子替代疗法-- 这可以预防、减轻、甚至逆转这种严重的糖尿病并发症。

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.