Role of Insulin-like Signaling in Glial Responses to Axon Degeneration

胰岛素样信号传导在神经胶质细胞对轴突变性反应中的作用

• 批准号: 8342453
• 负责人: Mary Allison Logan
• 金额: $ 32.73万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8342453
• 关键词: Acute; Adult; Affect; Alzheimer' s Disease; Amyotrophic Lateral Sclerosis; Autoimmune Diseases; Axon; Axotomy; Behavior; Binding; Biological Assay; Brain; Brain region; Cells; Chronic; Chronic Disease; Communication; Complex; Cues; Development; Disease; Drosophila genus; Employee Strikes; Ensure; Event; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Health; Immune; Immune response; Injury; Insulin; Invaded; Laboratories; Ligands; Link; Mediating; Mission; Molecular; Molecular Genetics; Morphology; Multiple Sclerosis; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurologic; Neurons; Parkinson Disease; Pathway interactions; Peptides; Proteins; Public Health; Reaction; Receptor Signaling; Recruitment Activity; Resolution; Role; Signal Pathway; Signal Transduction; Site; Somatomedins; Stress; System; Translations; Trauma; United States National Institutes of Health; Up-Regulation; Vertebrates; Work; base; central nervous system injury; fly; gene function; genetic manipulation; in vivo; in vivo Model; innate immune function; insight; migration; mutant; nerve injury; nervous system disorder; novel; receptor; receptor coupling; response; response to injury; therapeutic target; therapy development; tool

DESCRIPTION (provided by applicant): Glial cells respond potently to neuronal damage, as well as neurodegenerative disease, by displaying overt changes in morphology, gene expression, migration, and phagocytic activity. Dysfunctional responses contribute to the progression of devastating neurological diseases, such as Alzheimer's disease and Parkinson's disease, and can also promote the onset of some autoimmune disorders. Despite the importance of glia in defending brain health, remarkably little is known about the molecular underpinnings of responses to neuronal damage. A vital long-term goal is to understand how basic glial immune reactions are triggered in the adult brain in response to damaged and dying neurons. The core cellular events (e.g. glial migration to injury sites and phagocytic clearance of neuronal debris) are highly conserved across species and recent work is revealing striking molecular conservation, as well. This proposal uses a well- established adult axotomy assay in Drosophila to investigate the molecular features of glial reactions; the fly offers a tractable genetic system to manipulate gene expression and function with exquisite cellular and temporal precision in vivo. Our preliminary work has identified a novel role for the evolutionarily conserved Insulin/insulin-like growth factor (IGF)-Like Signaling (ILS) pathway in orchestrating glial reactions to axon injury. Based on our findings, we hypothesize that ILS regulates glial immune responses in two fundamental ways: (1) Basal ILS activity in adult glia ensures that glia express key genes (i.e. the Draper receptor and adaptor Ced-6) required to detect and carry out responses to axon damage, and (2) Acute activation of the ILS pathway at injury sites triggers rapid responses in local glia to ensure that damaged neurons are cleared from the CNS. This proposal will employ powerful genetic-molecular tools to investigate how the ILS pathway contributes to axotomy-induced functions in glia. We will: (Aim 1) define the role of Insulin-like Receptor (InR) activity in each step of the glial response to axotomy, including altered gene expression, glial recruitment to injury sites, and glial phagocytic activity; (Aim 2) determine how insulin-like peptides (ilps), the InR ligands, influence basal expression of Draper and Ced-6, as well as each step of the injury response in local glia; and (Aim 3) define the molecular signaling cascades downstream of InR that are coupled to these important glial responses. This work will provide critical mechanistic insight into how damaged neurons communicate with glia to elicit responses and elucidate intrinsic molecular pathways that control these essential glial functions. Our findings will also offer a novel framework for exploring ILS components as therapeutic targets to treat CNS injury, as well as chronic neurodegenerative conditions. PUBLIC HEALTH RELEVANCE: Glial cells, the primary immune responders in the brain, respond swiftly and powerfully to traumatic injury and to chronic neurodegenerative disease, and abnormal glial responses contribute to the progression of devastating neurological conditions, including multiple sclerosis, Alzheimer's disease, and amyotrophic lateral sclerosis. This proposal is relevant to public health because it will provide critically needed insight into te molecular and cellular signaling pathways by which damaged neurons elicit innate responses in glial cells. These discoveries will advance our understanding of neuron-glia communication in the brain, provide a springboard for the development of treatments to reduce the burden of neurological disorders and, thus, will be highly relevant to the NIH mission.

描述（由申请人提供）：神经胶质细胞通过在形态、基因表达、迁移和吞噬活性方面表现出明显的变化，对神经元损伤以及神经退行性疾病做出有效反应。功能失调的反应会导致破坏性神经系统疾病（例如阿尔茨海默病和帕金森病）的进展，并且还会促进某些自身免疫性疾病的发作。尽管神经胶质细胞在保护大脑健康方面很重要，但人们对神经元损伤反应的分子基础却知之甚少。一个重要的长期目标是了解成人大脑中如何触发基本的神经胶质免疫反应来响应受损和垂死的神经元。核心细胞事件（例如胶质细胞迁移到损伤部位和吞噬细胞清除 神经元碎片）在物种间高度保守，最近的工作也揭示了惊人的分子保守性。该提案在果蝇中使用成熟的成人轴切术测定法来研究神经胶质反应的分子特征；果蝇提供了一个易于处理的遗传系统，可以在体内以精确的细胞和时间精度操纵基因表达和功能。我们的初步工作已经确定了进化上保守的胰岛素/胰岛素样生长因子（IGF）样信号传导（ILS）途径在协调神经胶质细胞对轴突损伤的反应中的新作用。根据我们的发现，我们假设 ILS 通过两种基本方式调节神经胶质细胞免疫反应：（1）成年神经胶质细胞中的基础 ILS 活性确保神经胶质细胞表达检测和执行轴突损伤反应所需的关键基因（即 Draper 受体和适配器 Ced-6），以及（2）损伤部位 ILS 通路的急性激活触发局部神经胶质细胞的快速反应，以确保 受损的神经元从中枢神经系统中清除。该提案将采用强大的遗传分子工具来研究 ILS 通路如何促进神经胶质细胞轴切术诱导的功能。我们将：（目标 1）定义胰岛素样受体（InR）活性在神经胶质细胞对轴索切断术反应的每个步骤中的作用，包括改变基因表达、神经胶质细胞募集到损伤部位以及神经胶质细胞吞噬活性； （目标 2）确定如何 胰岛素样肽 (ilps)、InR 配体影响 Draper 和 Ced-6 的基础表达，以及局部神经胶质细胞损伤反应的每一步； （目标 3）定义与这些重要的神经胶质反应耦合的 InR 下游的分子信号级联。这项工作将为受损神经元如何与神经胶质细胞通讯以引发反应提供关键的机制见解，并阐明控制这些基本神经胶质细胞功能的内在分子途径。我们的研究结果还将提供一个新的框架，用于探索 ILS 成分作为治疗中枢神经系统损伤以及慢性神经退行性疾病的治疗靶点。 公共健康相关性：神经胶质细胞是大脑中的主要免疫反应者，对创伤性损伤和慢性神经退行性疾病做出快速而有力的反应，异常的神经胶质细胞反应会导致破坏性神经系统疾病的进展，包括多发性硬化症、阿尔茨海默病和肌萎缩侧索硬化症。该提案与公共卫生相关，因为它将提供对分子和细胞信号传导途径急需的洞察，受损神经元通过这些途径在神经胶质细胞中引发先天反应。这些发现将增进我们对大脑中神经元-胶质细胞通讯的理解，为开发减轻神经系统疾病负担的治疗方法提供跳板，因此与 NIH 的使命高度相关。