Analysis of neuropoietic cytokines and their receptors in diabetic neuropathy

描述(申请人提供)：糖尿病是美国的主要健康和经济负担。根据美国糖尿病协会的统计数据，美国有超过2500万人患有糖尿病，占总人口的8%以上。最常见的并发症之一是周围神经系统受损，这种情况被称为糖尿病神经病变，超过60%的糖尿病患者会发生这种情况。虽然神经病发生的确切机制尚未阐明，但它可能是由多种代谢反应介导的。细胞因子是一种小的多肽，最初被认为是免疫系统内的通信者，但对包括神经系统在内的许多细胞类型具有不同的作用。我们感兴趣的是一个特定的细胞因子家族，神经生成细胞因子家族，因为它的成员已知在神经系统和免疫系统中都有表达，并且在正常动物的神经系统损伤和修复中起着重要的作用。我们实验室最近的研究表明，随着糖尿病的发展，受体亚基LIFR和gp130在很早就显着上调。此外，我们还发现该家族中的两种细胞因子(白介素6和白血病抑制因子)受到不同程度的调节。因此，我们假设这个细胞因子家族的成员在外周糖尿病神经病变中发挥作用，本提案试图进一步确定它们在这一过程中的作用。这一建议验证了神经生成性细胞因子家族成员在外周糖尿病神经病变中起关键作用的假设。我们将确定糖尿病神经中哪些细胞表达细胞因子及其受体。我们将量化信号转导途径中涉及的蛋白质的变化，以及这些变化是否受到葡萄糖的调节。最后，我们将通过给糖尿病野生型和IL-6基因敲除小鼠注射重组IL-6来直接测量对IL-6的反应，然后将量化参与信号转导的蛋白质的水平 卡斯卡德。这些实验的潜在好处将是确定周围神经病变的其他介质的参与。糖尿病神经病变的有效治疗需要了解神经功能的分子基础的表达和调控。 公共卫生相关性：糖尿病患者的外周神经系统缺陷是常见的。超过60%的糖尿病患者会发展成某种形式的糖尿病神经病变。目前，治疗的基石在于维持良好的血糖控制，这往往是困难的。因此，迫切需要开发有效的治疗糖尿病神经病变的方法。替代或抑制生长因子/细胞因子可能是改善糖尿病神经病变的关键。

DESCRIPTION (provided by applicant): Diabetes is a major health and economic burden in the United States. According to statistics from the American Diabetes Association there are more than 25 million people or more than 8 percent of the population, in the US with diabetes. One of the most common complications is damage to the peripheral nervous system, a condition known as diabetic neuropathy that occurs in more than 60% of diabetics. While the precise mechanism responsible for the development of neuropathy has yet to be elucidated, it is likely mediated by a variety of metabolic responses. Cytokines are small polypeptides originally identified as communicators within the immune system but have diverse actions on many cell types including those of the nervous system. We are interested in a specific family of cytokines, the neuropoietic cytokine family, because its members are known to be expressed by both the nervous and immune systems and they are important in the response to nervous system injury and repair in normal animals. Recent studies from our laboratory indicate that the receptor subunits LIFR and gp130 are dramatically upregulated very early following the development of diabetes. In addition, we have shown that two of the cytokines (interleukin-6 and leukemia inhibitory factor) in this family are differentially regulated. We therefore hypothesize that members of this family of cytokines play a role in peripheral diabetic neuropathy and this proposal seeks to further define their role in this process. This proposal tests the hypothesis tha members of the neuropoietic cytokine family play a critical role in peripheral diabetic neuropathy. We will determine which cells in diabetic nerve express the cytokines and their receptors. We will quantify the changes in the proteins involved in the signal transduction pathway and whether these are regulated by glucose. Finally we will directly measure the response to IL-6 by administering recombinant IL-6 to diabetic wild-type and interleukin-6 knockout mice and then will quantify the levels of the proteins involved in the signal transduction cascade. The potential benefit resulting from these experiments will be to ascertain the involvement of additional mediators of peripheral neuropathy. Effective treatment of diabetic neuropathy will require an understanding of the expression and regulation of the molecular basis for nerve function. PUBLIC HEALTH RELEVANCE: Defects of the peripheral nervous system are common in patients with diabetes mellitus. More than 60% of diabetic patients will develop some form of diabetic neuropathy. Currently the cornerstone of treatment lies with the maintenance of good glucose control which is often difficult. Therefore, the development of effective treatments for diabetic neuropathy is urgently needed. Replacement or inhibition of growth factors/cytokines may be the key to ameliorating diabetic neuropathy.