Mechanisms of neuroprotection in diabetic peripheral neuropathy

项目摘要 糖尿病周围神经病变(DPN)是糖尿病患者周围神经病变的最常见原因 并导致严重的发病率，并伴随着相关的医疗费用。它影响高达30%的人 减少所有糖尿病患者的死亡率，并降低患者的生活质量。导致DPN中的主要缺陷 患者的症状是外周轴突远端变性，也称为垂死性轴索病症。 尽管存在一些对症疗法，但这些疗法只有部分有效，目前还没有 阻止或逆转轴突变性或疾病进展的治疗，除了严格的糖尿病 控制力。即使在糖尿病控制良好的患者中，DPN也可能进展，强调DPN的复杂生物学 糖尿病伴相关代谢综合征患者的轴突变性。 尽管糖尿病致死性轴突变性的潜在机制可能是 复杂且涉及多个受损的分子通路，最终导致轴突退化 导致轴突变性的成分包括与程序性轴突共享的关键分子参与者 退化。其中包括NAD+合成酶、NMNA2和NAD+降解酶Sarm1。 轴突变性需要激活Sarm1，但这种激活是如何调节的，目前仍不清楚 调查。几年前，我们采取了一种不同的方法来开发治疗靶点，以防止 周围神经病中的轴突变性。我们没有针对特定的路径，而是从一个 防止轴突退变的表型药物筛选和鉴定Sf3b2，一种 剪接体复合体在预防化疗药物引起的轴突变性中起着关键作用。 我们的初步研究表明，Sf3b2是Sarm1激活的上游，并提供了一种替代治疗方法 可避免Sarm1抑制的潜在非靶点副作用的靶点。 在这一应用中要检验的最重要的假设是，在 程序性轴突变性在糖尿病周围神经病变的发生发展中的重要作用 神经病变和以新药为靶点可能提供新的治疗机会。我们会 通过检测感觉神经元特异性基因缺失Sarm1和Sf3b2的影响来检验这些假说 高脂饮食诱导2型糖尿病周围神经病变的研究 Sf3b2的作用机制及III)检测EQ-6在DPN HFD模型中的作用。

Project Summary Diabetic peripheral neuropathy (DPN) is the most common cause of peripheral neuropathy in the developed world and cause significant morbidity with associated healthcare expenses. It affects up to 30% of all diabetic patients and reduces the quality of life of patients. The primary defect in DPN that results in patient symptoms is the distal degeneration of peripheral axons, also known as dying-back axonopathy. Although some symptomatic therapies exist, these are only partially effective and currently there is no treatment that halts or reverses the axon degeneration or disease progression apart from strict diabetic control. DPN may progress even in patients with good diabetic control, emphasizing the complex biology of axon degeneration in diabetic patients with associated metabolic syndrome. Although the underlying mechanisms of dying-back axon degeneration in diabetes is likely to be complex and involve multiple impaired molecular pathways, the eventual degradation of axonal components leading to axonal degeneration includes key molecular players shared with programmed axon degeneration. These include NAD+ synthesizing enzyme, NMNAT2 and NAD+ degrading enzyme, Sarm1. Activation of Sarm1 is required for axonal degeneration but how this activation is regulated is still under investigation. Several years ago, we took a different approach to developing therapeutic targets to prevent axonal degeneration in peripheral neuropathies. Instead of targeting a specific pathway, we started with a phenotypic drug screen to prevent axon degeneration and identified SF3B2, a component of the spliceosome complex as playing a key role in preventing axon degeneration caused by chemotherapy drugs. Our preliminary studies indicate SF3B2 is upstream of Sarm1 activation and offer an alternative therapeutic target that may spare potential off-target side effects of Sarm1 inhibition. The overarching hypothesis to be tested in this application is that molecules that play a key role in programmed axon degeneration are important in development and progression of diabetic peripheral neuropathy and that targeting them with a novel drug may offer new therapeutic opportunities. We will test these hypotheses by i) examining the effect sensory neuron specific genetic deletion Sarm1 and SF3B2 on development of peripheral neuropathy in high fat diet (HFD) model of type 2 diabetes; ii) identifying mechanism of action of SF3B2 and iii) testing the efficacy of EQ-6 in the HFD model of DPN.