A chemical biology approach to studying the role of SARM1 in a novel degradative pathway

研究 SARM1 在新型降解途径中作用的化学生物学方法

基本信息

批准号：
9924674
负责人：
Heather Starr Loring
金额：
$ 1.86万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-25 至 2021-01-09
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9924674
关键词：
Active Sites Axon Biological Assay Biology Catalysis Cell Death Cells Characteristics Chemicals Cryoelectron Microscopy Crystallization Crystallography Cytoprotection Degradation Pathway Development Disease Disease Progression Drug Targeting Electron Microscopy Facility Enzyme Inhibitor Drugs Enzymes Feedback Future Glutamic Acid Human Hydrolase In Vitro Interleukin Receptor Kinetics Knock-out Knowledge Label Laboratories Length Mediating Modeling NAD+ Nucleosidase Nerve Degeneration Neurodegenerative Disorders Neurons Neuropathy Niacinamide Onset of illness Pathway interactions Pattern Play Process Property Proteins Reaction Research Role Series Sterility Structure Synapses Toxic effect Traumatic Brain Injury Treatment Efficacy Wallerian Degeneration X-Ray Crystallography activity-based protein profiling axonal degeneration base design drug development experimental study in vivo inhibitor/antagonist insight knock-down mutant neuron loss new therapeutic target novel prevent success therapeutic target

项目摘要

Project Summary The novel NAD glycohydrolase, SARM1, is an active executioner in progressive axonal and neuronal degeneration1. This type of degeneration, termed Wallerian degeneration, defines a number of diseases, including neuropathies, traumatic brain injury and neurodegenerative diseases, yet no therapies exist. In fact, prior to the discovery of SARM1’s role in triggering Wallerian degeneration, the process was believed to occur passively. SARM1’s causal role in Wallerian degeneration demonstrates that it is an attractive therapeutic target that could prevent disease progression. However, the design of therapeutics targeting SARM1 is limited by the dearth of knowledge surrounding its inherent NADase activity. In order to evaluate SARM1’s therapeutic efficacy and design potential SARM1 inhibitors, the proposed research will study its structure, enzymatic mechanism and cellular activity. Solving the structure by leveraging the benefits of crystallography and cryoEM, determining the enzymatic mechanism via a series of assays and analyzing the in vivo activity with activity-based probes will fill in important gaps. Revealing these properties would enable the design of SARM1 inhibitors that could ultimately treat Wallerian-type diseases. Moreover, demystifying the role SARM1 plays in neurodegeneration would also allow for a better understanding of these disease types, the enzymatic capabilities of toll/interleukin receptor (TIR) domains and the involvement of NADases in numerous disease states.

项目摘要新颖的NAD GlyDrololase SARM1是渐进式轴突和神经元的活跃execution子手变性1。这种类型的变性称为Wallerian变性，定义了许多疾病，包括神经病，创伤性脑损伤和神经退行性疾病，但不存在疗法。实际上，在发现SARM1在触发Wallerian变性中的作用之前，据信这一过程发生被动 SARM1在沃勒（Wallerian）变性中的因果作用表明，这是一个有吸引力的治疗靶标的预防疾病进展。但是，针对SARM1的理论设计的设计受到死亡的限制围绕其固有的NADase活动的知识。为了评估SARM1的治疗效率和设计潜在的SARM1抑制剂，拟议的研究将研究其结构，酶促机制和细胞活性。通过利用晶体学和冷冻的好处来解决结构，确定通过一系列测定法进行酶促机制，并分析具有基于活动的问题的体内活性在重要差距中。揭示这些特性将使SARM1抑制剂的设计最终可以治疗Wallerian型疾病。此外，神经退行性中SARM1在神经变性中扮演的角色也将可以更好地了解这些疾病类型，即Toll/白介素受体的酶促能力（TIR）领域和纳adase在许多疾病状态中的参与。