Mechanisms of neuroprotection in diabetic peripheral neuropathy

糖尿病周围神经病变的神经保护机制

基本信息

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
项目类别：
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

项目摘要

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.

项目概要糖尿病周围神经病变（DPN）是糖尿病周围神经病变的最常见原因发达国家并导致显着的发病率和相关的医疗费用。影响高达30% 影响所有糖尿病患者并降低患者的生活质量。 DPN 的主要缺陷导致患者的症状是周围轴突的远端变性，也称为垂死性轴突病。尽管存在一些对症疗法，但这些疗法仅部分有效，目前还没有除严格糖尿病外，停止或逆转轴突变性或疾病进展的治疗控制。即使糖尿病控制良好的患者，DPN 也可能会进展，这强调了 DPN 的复杂生物学特性。患有相关代谢综合征的糖尿病患者的轴突变性。尽管糖尿病死亡轴突变性的潜在机制可能是复杂并涉及多个受损的分子途径，轴突的最终降解导致轴突变性的成分包括与编程轴突共享的关键分子参与者退化。其中包括 NAD+ 合成酶 NMNAT2 和 NAD+ 降解酶 Sarm1。轴突变性需要激活 Sarm1，但如何调节这种激活仍不清楚调查。几年前，我们采取了不同的方法来开发治疗靶点以预防周围神经病中的轴突变性。我们没有针对特定的途径，而是从一个预防轴突变性的表型药物筛选并鉴定了 SF3B2，它是剪接体复合物在预防化疗药物引起的轴突变性中发挥着关键作用。我们的初步研究表明 SF3B2 是 Sarm1 激活的上游并提供替代治疗可能避免 Sarm1 抑制潜在的脱靶副作用的目标。本申请要测试的首要假设是，在以下过程中发挥关键作用的分子：程序性轴突变性对于糖尿病外周血管疾病的发生和进展很重要神经病以及针对它们的新药可能会提供新的治疗机会。我们将通过 i) 检查感觉神经元特异性基因缺失 Sarm1 和 SF3B2 的影响来检验这些假设 2 型糖尿病高脂饮食 (HFD) 模型中周围神经病变的发展； ii) 识别 SF3B2 的作用机制和 iii) 测试 EQ-6 在 DPN 的 HFD 模型中的功效。