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

• 批准号: 8077253
• 负责人: Martha Ruth Chase Bhattacharya
• 金额: $ 1.18万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 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/8077253
• 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

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）：轴突变性导致糖尿病、青光眼和帕金森病的病理，并且是化疗治疗的剂量限制副作用。它是一个主动调控的程序，类似于细胞凋亡，但其执行机制不同。控制轴突保存和破坏的细胞程序尚不清楚，我们目前还没有预防这种退化的治疗方法。治疗或预防轴突变性的疗法的发展可以显著改善上述疾病患者的生活质量，同时也减轻了他们对我们的医疗保健系统的负担。目前已知有两个基因影响神经元轴突变性：wds和MAP激酶DLK。在损伤模型中，抑制DLK或其下游激酶JNK可显著延缓轴突变性。我建议研究由DLK控制的允许这种延迟的细胞机制。我将在体外培养初级体感觉神经元，在培养中损伤轴突，并使用细胞测定、共聚焦显微镜和生物化学来研究DLK如何调节微管、轴突运输和其他受轴突退化影响的途径。DLK和wds通路的交叉也将被研究，因为这两种控制机制可能以一种加性的方式起作用，并且可以为设计轴突变性的分子疗法提供额外的见解。为此，我们将在体外和体内使用已经建立的转基因小鼠和慢病毒感染的神经元。最后，我将测试DLK或JNK抑制是否控制了组成视神经的视网膜神经节细胞（RGCs）轴突的变性，因为这些轴突在青光眼期间发生变性。RGCs的体外研究和体内损伤模型，以及已建立的青光眼小鼠模型，都将用于研究DLK和/或wds是否在该系统中发挥保护作用，以及DLK通路抑制是否可能是青光眼的适当治疗策略。了解轴突变性将有显著的公共卫生效益，由于广泛的疾病，轴突变性引起的症状。我们的研究旨在确定有效的途径延迟或预防轴突变性，可用于临床设置