The role of sciatic nerve inflammation in diabetic neuropathy

摘要 糖尿病神经病变(DN)的特征是周围感觉神经轴突终末回缩。 以“手套和袜子”为图案的目标。然而，糖尿病肾病的机制仍然不清楚，阻碍了成功 治疗性干预。与1型糖尿病不同，2型糖尿病伴有全身新陈代谢 功能障碍可能参与糖尿病肾病的发生发展。许多患者在糖尿病前期出现神经病变 高脂血症、高血糖和胰岛素抵抗都会损害细胞膜的完整性、轴突生长和 感觉神经元中的线粒体运动。代谢综合征的另一个重要标志是全身性 炎性巨噬细胞参与的低度炎症。巨噬细胞是沃勒氏病的主要参与者 在清除碎片以及从坐骨神经损伤和再生中恢复方面起着重要作用。 目前尚不清楚坐骨神经中的巨噬细胞是否参与或反应了糖尿病神经病变。 我在初步数据中发现，糖尿病前期小鼠表现出热过敏和皮肤神经减少， 尤其是CGRP纤维。我还发现糖尿病前期的小鼠坐骨神经炎症增加 回想起对坐骨神经损伤的即时反应，包括CCL2上调和CD68增加 在巨噬细胞中。 在这里，我打算研究坐骨神经巨噬细胞是否以及如何参与糖尿病神经病变或反应轴突。 退化。我推测SCN巨噬细胞参与了2型糖尿病的发病。 神经病。在第一个目标中，我将确定CCL2驱动的巨噬细胞向神经的募集 导致热过敏症的发生。在第二个目标中，我将确定是否持续 坐骨神经中CD68巨噬细胞/CCL2信号的增加参与了坐骨神经的持续性失神经 糖尿病前期小鼠皮肤及CCR2受体阻滞剂能否挽救失神经。最后，我会 确定小的无髓鞘c纤维是否经历了损伤的转录重编程，以及损伤的程度 低度炎症参与了DRG神经元转录的改变。 这项研究将提高我们对免疫系统是否以及如何参与糖尿病的发生发展的理解。 周围神经病，这在很大程度上仍然是未知的。此外，这项研究还将确定相似程度 糖尿病神经病变是坐骨神经损伤模型在转录重编程方面的应用。建议数 这项工作可能会为糖尿病前期神经病变开辟新的治疗途径，这是一个重大的临床挑战，只有 增加，并将提高我们对感觉神经元如何应对代谢功能障碍的了解。

Abstract Diabetic neuropathy (DN) is characterized by the retraction of sensory axon terminals in the periphery from their targets with a “glove and stocking” pattern. The mechanisms of DN remain though, unclear, impairing successful therapeutic interventions. Unlike type 1 diabetes, type 2 diabetes is accompanied by a systemic metabolic dysfunction that may contribute to the development of DN. Many patients develop neuropathy while pre-diabetic and hyperlipidemia, hyperglycemia, and insulin resistance all impair membrane integrity, axon growth, and mitochondrial motility in sensory neurons. Another important hallmark of the metabolic syndrome is systemic low-grade inflammation involving inflammatory macrophages. Macrophages are major players in Wallerian degeneration and have roles in debris clearance as well as recovery from sciatic nerve injury and regeneration. Whether macrophages in the sciatic nerve contribute or react to diabetic neuropathy is unexplored. I find in preliminary data that pre-diabetic mice exhibit heat hyposensitivity and decreased skin innervation, especially for CGRP+ fibers. I also find that pre-diabetic mice have an increased sciatic nerve inflammation reminiscent of the immediate response to sciatic nerve injury including, CCL2 upregulation and CD68 increase in macrophages. Here, I propose to study if and how sciatic nerve macrophages contribute to diabetic neuropathy or react o axon degeneration. I hypothesize that SCN macrophages contribute to the pathogenesis of type 2 diabetic neuropathy. In the first aim, I will determine whether CCL2-driven recruitment of macrophages to the nerve contributes to the onset of heat hyposensitivity. In the second aim, I will determine whether the sustained increase in CD68+ macrophages/CCL2 signaling in the sciatic nerve contributes to the sustained denervation of the skin of pre-diabetic mice and whether the denervation can be rescued by CCR2 blockade. Finally, I will determine whether small unmyelinated c-fibers undergo injury transcriptional reprogramming and to what extent low-grade inflammation contributes to the DRG neuron transcriptional changes. This study will improve our understanding of if and how the immune system is involved in the development of peripheral neuropathies, which remains largely unknown. In addition, this study will also determine how similar diabetic neuropathy is to sciatic nerve injury models in terms of transcriptional reprogramming. The proposed work could open new therapeutic avenues for pre-diabetic neuropathy, a significant clinical challenge that is only increasing, and will improve our knowledge of how sensory neurons respond to metabolic dysfunction.