The role of sciatic nerve inflammation in diabetic neuropathy

摘要 糖尿病性神经病变（DN）的特征在于外周中的感觉轴突末梢从它们的轴突末梢回缩。 用“手套和袜子”的模式瞄准目标。DN的发病机制尚不清楚， 治疗干预。与1型糖尿病不同，2型糖尿病伴随全身代谢紊乱， 可能导致DN发展的功能障碍。许多患者在糖尿病前期时发生神经病变 高脂血症、高血糖症和胰岛素抵抗都会损害膜的完整性、轴突的生长， 感觉神经元的线粒体运动。代谢综合征的另一个重要特征是全身性的 涉及炎性巨噬细胞的低度炎症。Macrophages是Wallerian的主要参与者 在坐骨神经损伤和再生中具有碎片清除以及恢复的作用。 坐骨神经中的巨噬细胞是否对糖尿病性神经病变起作用或起反应还未研究。 我在初步数据中发现，糖尿病前期小鼠表现出热敏感性降低和皮肤神经支配减少， 尤其是CGRP+纤维。我还发现糖尿病前期小鼠的坐骨神经炎症增加 让人想起对坐骨神经损伤的立即反应，包括CCL 2上调和CD 68增加 在巨噬细胞中。 在这里，我建议研究坐骨神经巨噬细胞是否以及如何促进糖尿病神经病变或对轴突反应。 退化我推测SCN巨噬细胞参与了2型糖尿病的发病机制。 神经病变在第一个目标中，我将确定CCL 2驱动的巨噬细胞向神经的募集是否 会导致热敏感性降低在第二个目标中，我将确定持续的 坐骨神经中CD 68+巨噬细胞/CCL 2信号传导的增加有助于持续的去神经支配， 糖尿病前期小鼠的皮肤以及CCR 2阻断是否可以挽救去神经支配。最后要 确定小的无髓鞘c纤维是否经历损伤转录重编程以及在多大程度上 低度炎症导致DRG神经元转录变化。 这项研究将提高我们对免疫系统是否以及如何参与发展的理解。 周围神经病变，这在很大程度上仍然未知。此外，这项研究还将确定如何类似 糖尿病神经病变是坐骨神经损伤模型在转录重编程方面。拟议 这项工作可能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， 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认识。

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.