Mechanisms of Axonal Degeneration in Traumatic Injury and Neurological Disease

创伤性损伤和神经系统疾病中轴突变性的机制

基本信息

批准号：
7674866
负责人：
Martha Ruth Chase Bhattacharya
金额：
$ 4.72万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-19 至 2011-09-18
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7674866
关键词：
Adverse effects Affect Animal Disease Models Animal Model Apoptosis Axon Axonal Transport Biochemistry Biological Preservation Carrier Proteins Cellular Assay Chimeric Proteins Clinical Code Confocal Microscopy Diabetes Mellitus Disease Dissociation Dose-Limiting Enzymes Excision Genes Glaucoma Health Benefit Healthcare Systems In Vitro Infection Injury JNK-activating protein kinase Kinesin MAP Kinase Kinase Kinase MAPK8 gene Microtubules Mitogen-Activated Protein Kinases Modeling Molecular Molecular Motors Multiple Sclerosis Mus Mutation Nerve Nerve Degeneration Neurons Optic Nerve Parkinson Disease Pathology Pathway interactions Patients Phosphotransferases Prevention Process Proteins Public Health Quality of life Regulation Research Retinal Ganglion Cells Role Signal Transduction Symptoms Synapses System Testing Therapeutic Transgenic Mice anterograde transport axonal degeneration design fly improved in vivo inhibitor/antagonist injured insight knockout animal mouse model nervous system disorder prevent programs protective effect somatosensory therapy development

项目摘要

DESCRIPTION (provided by applicant): Axon degeneration contributes to the pathologies of diabetes, glaucoma, and Parkinson's Disease, and is the dose-limiting side effect of chemotherapeutic treatments. It is an actively regulated program similar to apoptosis but distinct in its execution mechanisms. Cellular programs controlling the preservation and destruction of axons are not well understood, and we do not currently have therapies to prevent such degeneration. Development of therapies to treat or prevent axon degeneration could significantly improve the quality of life for patients with the above disorders while also reducing the burden they place on our health care system. Two genes are currently known to influence axon degeneration in neurons: Wlds, and the MAP kinase DLK. Inhibition of DLK or its downstream kinase JNK significantly delay axon degeneration in injury models. I propose to investigate the cellular mechanisms controlled by DLK that allow this delay. I will culture primary somatosensory neurons in vitro, injure axons in culture, and use cellular assays, confocal microscopy, and biochemistry to ask how DLK regulates microtubules, axon transport, and other pathways affected by axon degeneration. The intersection of the DLK and Wlds pathways will also be examined, as these two control mechanisms may act in an additive manner and could provide additional insight into designing molecular therapies for axon degeneration. For this aim we will use already established transgenic mice and lentiviral infection of neurons in vitro and in vivo. Finally, I will test whether DLK or JNK inhibition control degeneration in axons of retinal ganglion cells (RGCs) comprising the optic nerve, as these axons undergo degeneration during glaucoma. Both in vitro studies of RGCs and in vivo injury models, as well as established mouse models of glaucoma, will be used to ask whether DLK and/or Wlds exert protective effects in this system and whether DLK pathway inhibition may be an appropriate therapeutic strategy for glaucoma. Understanding axon degeneration will have significant public health benefits due to the broad spectrum of diseases where axon degeneration causes symptoms. Our research seeks to determine effective avenues for delay or prevention of axon degeneration that could be used in clinical settings

描述（由申请人提供）：轴突变性有助于糖尿病，青光眼和帕金森氏病的病理，并且是化学治疗的剂量限制副作用。它是一个类似于凋亡的积极调节程序，但其执行机制与众不同。控制轴突的保存和破坏的蜂窝程序尚不清楚，我们目前没有疗法来防止这种变性。开发治疗或预防轴突变性的疗法可以显着改善上述疾病患者的生活质量，同时减轻他们在我们的医疗保健系统上的负担。目前已知两个基因会影响神经元中的轴突变性：WLDS和MAP激酶DLK。 DLK或其下游激酶JNK的抑制显着延迟了损伤模型中的轴突变性。我建议研究由DLK控制的细胞机制，这些机制允许此延迟。我将在体外培养原发性体感神经元，培养培养基中的轴突，并使用细胞测定，共聚焦显微镜和生物化学来询问DLK如何调节微管，轴突转运和其他受轴突变性影响的途径。还将检查DLK和WLDS途径的交点，因为这两种控制机制可能会以添加剂方式起作用，并且可以为设计分子疗法的轴突变性提供更多见解。为此，我们将在体外和体内使用已经建立的转基因小鼠和神经元的慢病毒感染。最后，我将测试构成视神经的视网膜神经节细胞（RGC）中DLK或JNK抑制控制变性，因为这些轴突在青光眼期间经历了变性。对RGC和体内损伤模型的体外研究以及已建立的小鼠青光眼模型都将用于询问DLK和/或WLDS是否在该系统中发挥保护作用，以及DLK途径抑制是否可能是适当的治疗策略。由于轴突变性引起症状的广泛疾病，了解轴突变性将具有显着的公共卫生益处。我们的研究旨在确定可用于临床环境的延迟或预防轴突变性的有效途径