gp130 Cytokines, Diabetic Autonomic Neuropathy, and Nerve Regeneration

描述(由申请人提供)：超过8%的美国人患有1型或2型糖尿病，超过两倍的人患有前驱糖尿病。周围神经病变是“垂死性神经病变”的一个例子，是一种在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)是一种常见的疾病，可导致房颤、中风和不明原因的猝死等一系列疾病，因此开发治疗方法势在必行。然而，DAN的分子基础尚不清楚，这一知识对于预防和可能逆转这种神经病变至关重要。此外，大多数关于糖尿病的动物研究都集中在感觉神经元和运动神经元上。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，如果能够恢复正常的再生，可以弥补由于高血糖导致的正在进行的轴突退化。现在人们对促进正常动物再生的信号了解很多，但这些进展还没有被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有20年。着眼于条件性损伤后再生相关基因(RAG)表达的变化和生长能力的增加，我们发现这些反应中的许多依赖于gp130细胞因子家族中的损伤诱导的炎性细胞因子。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损伤后基因表达的特定变化中以及在正常交感神经元的条件性损伤反应中起着强制性作用。我们建议利用我们在正常动物身上学到的教训，在体内和体外的小鼠糖尿病模型系统中研究DAN的病因(S)和潜在的治疗方法(S)。这一建议的中心假设如下：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/或受损神经元的细胞因子反应性降低而导致gp130细胞因子信号的减少。这些改变导致RAG表达减少，轴突生长减少，再生减少，终末器官功能恢复减慢，这些缺陷可能被细胞因子替代治疗所逆转。利用这些小鼠模型，我们建议使用神经移植技术来研究交感神经节中细胞因子的表达和反应的调节，已知的对神经再生重要的基因的表达，再生的程度，以及内在和外在因素的作用。 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通过应用这些细胞因子来改善。我们预计，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潜在原因，并有望导致治疗--如细胞因子替代疗法--可以预防、减少甚至逆转糖尿病的这一严重并发症。

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.