Sarm1 Pathway: New Therapeutic Targets in Neuropathy

Sarm1 通路：神经病的新治疗靶点

• 批准号: 8868459
• 负责人: Stefanie Geisler
• 金额: $ 16.44万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8868459
• 关键词: Acute; Adverse effects; Alzheimer' s Disease; Apoptosis; Axon; Axotomy; Basic Science; Behavioral; Biochemical; Cessation of life; Chronic; Clinical; Disease; Dose-Limiting; Foundations; Funding; Genes; Goals; Human; In Vitro; Inherited; K-Series Research Career Programs; Knock-out; Knockout Mice; Knowledge; Life; Link; Mediating; Medicine; Mentors; Methods; Mitochondria; Modeling; Molecular; Molecular Genetics; Natural regeneration; Neuraxis; Neurodegenerative Disorders; Neurons; Neuropathy; Parkinson Disease; Pathway interactions; Patients; Peripheral; Peripheral Nervous System Diseases; Physicians; Play; Process; Proteins; Public Health; Research; Research Training; Role; Scientist; Signal Pathway; Spinal Ganglia; System; Therapeutic; Therapeutic Agents; Time; Toll-like receptors; Training Support; Translating; United States; Vincristine; Wallerian Degeneration; axonal degeneration; base; cellular imaging; chemotherapeutic agent; chemotherapy induced neuropathy; clinically relevant; genome-wide analysis; in vivo; insight; knock-down; nervous system disorder; neuromuscular; neurotoxicity; new therapeutic target; novel; novel therapeutics; prevent; programs; protective effect; protein function; public health relevance; research study; skills; small hairpin RNA; therapeutic target; treatment strategy

 DESCRIPTION (provided by applicant): The goal of this mentored career development award is to facilitate the PI's transition to independence as a physician-scientist with clinical expertie in neuromuscular medicine and a research emphasis in the molecular mechanisms of peripheral neuropathies. The proposed research, to be conducted under the guidance of primary mentor Dr. Aaron DiAntonio, will evaluate Sarm1 as a therapeutic target in neuropathies, identify other components of the Sarm1 axon destruction pathway and investigate how components downstream of Sarm 1 interact with it and each other to control axon degeneration (AxD). AxD is a prominent feature of most neuropathies and also occurs early in several other neurodegenerative disorders. However, no treatments currently exist that target axonal degeneration specifically. Recently, it was discovered that knocking down the Toll-like receptor adaptor Sarm1 dramatically protects axons from acute degeneration after axotomy. This clearly implicates Sarm1 as an effector in the pathway mediating acute AxD and gives hope that inhibition of Sarm1 and its downstream components may be useful therapeutically. However, a major limitation for translating Sarm1 into candidate therapeutics is our lack of knowledge of the molecular mechanisms that underlie its axodestructive actions. In view of these considerations we propose a research program guided by the following specific aims: 1) Determine, using behavioral, electrodiagnostic and histopathological methods, if Sarm1 knock out ameliorates vincristine induced neuropathy 2) Identify proteins that function downstream in the Sarm1 destructive pathway using a candidate-based suppressor screen in dorsal root ganglion neurons. 3) Investigate the functional interactions of Sarm1 and a recently identified suppressor (Fbxo7) using biochemical, anatomical, and molecular genetics methods in combination with live cell imaging. The proposed experiments are expected to reveal previously unknown mechanisms of AxD and identify new therapeutic targets in neuropathies. The research training supported by the requested funds will parallel the PI's clinical focus in neuromuscular medicine and provide a skill set and possibly new therapeutic agents for translating basic science discoveries into treatment strategies relevant to patients with neuropathies and possibly other neurodegenerative diseases.

 描述（由申请人提供）：该指导职业发展奖的目标是促进PI作为一名具有神经肌肉医学临床专业知识和周围神经病变分子机制研究重点的医生-科学家向独立过渡。这项拟议的研究将在主要导师Aaron DiAntonio博士的指导下进行，将评估Sarm 1作为神经病的治疗靶点，确定Sarm 1轴突破坏途径的其他成分，并研究Sarm 1下游的成分如何与它相互作用，以控制轴突变性（AxD）。AxD是大多数神经病变的突出特征，也在其他几种神经退行性疾病中早期发生。然而，目前还没有专门针对轴突变性的治疗方法。最近，人们发现，敲低Toll样受体接头SARM 1显着保护轴突从急性变性后轴突切断。这清楚地表明Sarm 1是介导急性AxD的途径中的效应子，并为抑制Sarm 1及其下游成分可能在治疗上有用带来了希望。然而，将Sarm 1翻译成候选疗法的一个主要限制是我们缺乏对其轴突破坏作用的分子机制的了解。鉴于这些考虑，我们提出了一个由以下具体目标指导的研究计划：1）使用行为、电诊断和组织病理学方法确定Sarm 1敲除是否改善了长春新碱诱导的神经病变; 2）使用背根神经节神经元中基于候选物的抑制剂筛选来鉴定在Sarm 1破坏性通路下游起作用的蛋白质。3)研究Sarm 1和最近发现的抑制因子（Fbxo 7）的功能相互作用，使用生物化学，解剖学和分子遗传学方法结合活细胞成像。预计拟议的实验将揭示AxD以前未知的机制，并确定神经病的新治疗靶点。所申请资金支持的研究培训将与PI在神经肌肉医学方面的临床重点平行，并提供一套技能和可能的新治疗药物，用于将基础科学发现转化为与神经病变和可能的其他神经退行性疾病患者相关的治疗策略。