Mechanisms of neuroprotection in diabetic peripheral neuropathy

糖尿病周围神经病变的神经保护机制

• 批准号: 10355923
• 负责人: Ahmet Hoke
• 金额: $ 53.94万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10355923
• 关键词: Affect; Afferent Neurons; Axon; Back; Biology; Blood; Cells; Complex; Defect; Development; Diabetes Mellitus; Diabetic Neuropathies; Disease Progression; Distal; Drug Kinetics; Drug Screening; Enzymes; Genetic; Healthcare; High Fat Diet; Impairment; Investigation; Measures; Mediating; Metabolic syndrome; Metabolism; Modeling; Molecular; Morbidity - disease rate; Mus; Nerve Degeneration; Neurons; Neuropathy; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Patients; Peripheral; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Phenotype; Play; Proteins; Quality of life; Risk; Role; Safety; Spliceosomes; Symptoms; Testing; Therapeutic; Tissues; analog; axonal degeneration; axonopathy; chemotherapy; conditional knockout; diabetic; diabetic patient; drug candidate; efficacy evaluation; efficacy testing; macrophage; metabolic abnormality assessment; nerve damage; neuroprotection; novel; novel therapeutics; preclinical safety; prevent; side effect; targeted biomarker; therapeutic target

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.

项目摘要 糖尿病周围神经病（DPN）是外周神经病的最常见原因 发达的世界，并引起相关的医疗费用的大量发病率。它影响高达30％ 在所有糖尿病患者中，并降低了患者的生活质量。 DPN中的主要缺陷导致 患者症状是外周轴突的远端变性，也称为垂死的轴突病。 尽管存在某些症状疗法，但这些疗法仅是部分有效的，目前没有 除了严格的糖尿病外，可以停止或逆转轴突变性或疾病进展的治疗 控制。即使在具有良好糖尿病控制的患者中，DPN也可能进展，强调了复杂的生物学 与代谢综合征的糖尿病患者的轴突变性。 尽管糖尿病中垂死的轴突变性的基本机制可能是 复合物并涉及多个分子途径，轴突的最终降解 导致轴突变性的组件包括与编程轴突共享的关键分子玩家 退化。其中包括NAD+合成酶，NMNAT2和NAD+降解酶，SARM1。 轴突变性需要SARM1的激活，但是如何调节这种激活仍在 调查。几年前，我们采取了不同的方法来开发治疗靶标的 周围神经病的轴突变性。我们没有针对特定途径，而是从 表型药物筛查以防止轴突变性并鉴定出SF3B2，这是 剪接体复合物是在预防化学疗法药物引起的轴突变性方面发挥关键作用。 我们的初步研究表明SF3B2是SARM1激活的上游，并提供了替代性治疗 可能避免SARM1抑制的潜在副作用的目标。 在此应用中要测试的总体假设是在 编程的轴突变性在糖尿病周围的发育和发展中很重要 神经病和用新药物将其瞄准的神经病可能会提供新的治疗机会。我们将 通过i）检查这些假设，检查感觉神经元特异性遗传缺失SARM1和SF3B2 关于2型糖尿病的高脂饮食中周围神经病（HFD）模型的发展； ii）识别 SF3B2和III的作用机理测试EQ-6在DPN的HFD模型中的功效。