Analysis of neuropoietic cytokines and their receptors in diabetic neuropathy

描述（由申请人提供）：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2500万人或超过8%的人口患有糖尿病。最常见的并发症之一是周围神经系统损伤，这种情况被称为糖尿病神经病变，发生在60%以上的糖尿病患者中。虽然神经病变发展的确切机制尚未阐明，但它可能是由多种代谢反应介导的。细胞因子是最初被鉴定为免疫系统内的通讯者的小多肽，但对许多细胞类型（包括神经系统的细胞类型）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，神经细胞因子家族，因为它的成员是已知的神经和免疫系统的表达，他们是重要的神经系统损伤和修复正常动物的反应。我们实验室最近的研究表明，受体亚基LIFR和gp 130在糖尿病发展后的非常早期显著上调。此外，我们已经表明，两个细胞因子（白细胞介素-6和白血病抑制因子）在这个家庭的差异调节。因此，我们假设这个家族的细胞因子的成员在周围糖尿病神经病变中发挥作用，这个建议旨在进一步确定他们在这个过程中的作用。该建议验证了神经生成细胞因子家族成员在糖尿病周围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。我们将量化参与信号转导途径的蛋白质的变化，以及这些蛋白质是否受葡萄糖的调节。最后，我们将通过将重组IL-6给予糖尿病野生型和白细胞介素-6敲除小鼠来直接测量对IL-6的应答，然后将量化参与信号转导的蛋白质的水平。 级联。这些实验的潜在益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节。 公共卫生相关性：周围神经系统缺陷在糖尿病患者中很常见。超过60%的糖尿病患者会出现某种形式的糖尿病神经病变。目前，治疗的基础在于维持良好的血糖控制，这通常是困难的。因此，迫切需要开发有效的糖尿病神经病变治疗方法。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.