Xenon gas treatment to modulate microglia in neurodegenerative diseases

氙气治疗调节神经退行性疾病中的小胶质细胞

• 批准号: 10259094
• 负责人: Oleg Butovsky
• 金额: $ 49.95万
• 依托单位: GENERAL BIOPHYSICS, LLC
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10259094
• 关键词: APP-PS1; Ablation; Acute; Address; Affect; Aging; Alzheimer like pathology; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease therapy; Amyloid beta-Protein; Anesthetics; Apolipoprotein E; Apoptosis; Apoptotic; Axon; Biology; Blood - brain barrier anatomy; Brain; Brain Injuries; Cell model; Cells; Collaborations; Data; Development; Disease; Disease Progression; Equilibrium; Functional disorder; Gases; Genes; Genetic; Genetic Transcription; Goals; Health; Hemostatic Agents; Homeostasis; Human; Immune; Immune system; Inflammatory; Inhalation; Inhalation Device; Legal patent; MADH3 gene; Maintenance; Mediating; Methods; Microglia; Molecular Profiling; Mus; Nerve Degeneration; Neurodegenerative Disorders; Neurons; Neuroprotective Agents; Noble Gases; Pathogenicity; Pathway Analysis; Patients; Pattern; Phagocytes; Phagocytosis; Phenotype; Play; Protocols documentation; Regulation; Role; Senile Plaques; Signal Transduction; Small Business Technology Transfer Research; System; Technology; Therapeutic; Transforming Growth Factor beta; Transgenic Mice; Treatment Protocols; Work; Xenon; base; brain health; design; dimer; genetic risk factor; human subject; immunoregulation; in vivo; mouse model; muscle enhancer factor-2A; neurodegenerative phenotype; neuron apoptosis; novel; preservation; programs; protective effect; prototype; repaired; restoration; sensor; tau Proteins; therapeutically effective; tool

PHASE I APPLICATION (STTR Program PAS-19-317) “Xenon gas treatment to modulate microglia in neurodegenerative diseases” ABSTRACT Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder. Emerging evidence shows that homeostatic dysregulation of the brain immune system, especially that orchestrated by microglia, plays a significant role in the onset and progression of the disease. The microglial function is maintained in healthy brain and is pathogenically dysregulated in AD brain. The prominent genetic risk factors, APOE, is involved in microglial function. We have recently identified a unique molecular signature for homeostatic microglia and have developed robust tools to investigate microglial biology in health and disease. We also identified a role for the APOE-signaling in the regulation of a new microglial subset associated with neurodegeneration and in microglia surrounding neuritic Ab-plaques in human AD brain, which we have termed MGnD. The major question relates to microglia-based approach to treat AD is how to modulate microglia phenotype and function. Preservation of neuronal cells from Aβ induced apoptosis as well as restoration of resident microglial homeostatic function is critical for the restoration of brain function. The goal of this proposal is to validate the Xenon (Xe) gas ability to modulate microglia in AD mouse model and human, that will lead to development of novel AD treatment. Xe is currently used in human patients as an anesthetic and as a neuroprotectant in treatment of brain injuries. Xe penetrates blood brain barrier, which can make it effective therapeutic. Our preliminary data demonstrated in acute and AD mouse models that Xe delivered through inhalation modulates brain microglia and preserve it in the hemostatic form. In this proposal we would like to further validate Xe action on microglia in-vivo in AD mice model and in neurogenerative human microglia. We will address our hypothesis in the following aims: Aim 1: Investigate whether Xe-gas treatment affects phenotype and function of neurodegenerative microglia in APP-PS1 mice. Aim 2: Validate whether Xe-gas treatment affects phenotype and function of neurodegenerative human microglia. Based on results of these work we will be able to develop the inhalation system and protocol for implementation of the therapeutic method for AD treatment.

第一阶段申请 （STTR 计划 PAS-19-317） “氙气治疗调节神经退行性疾病中的小胶质细胞” 抽象的 阿尔茨海默病（AD）是最常见的神经退行性疾病。新出现的证据表明 大脑免疫系统的稳态失调，尤其是由小胶质细胞精心策划的失调，起着 在疾病的发生和发展中发挥着重要作用。健康大脑中维持小胶质细胞功能 AD 脑中致病性失调。突出的遗传风险因素 APOE 涉及 小胶质细胞功能。我们最近发现了稳态小胶质细胞的独特分子特征，并已 开发了强大的工具来研究健康和疾病中的小胶质细胞生物学。我们还确定了一个角色 APOE 信号传导在与神经变性相关的新小胶质细胞亚群和小胶质细胞中的调节 人类 AD 大脑中神经炎性 Ab 斑块周围，我们称之为 MGnD。主要问题涉及 以小胶质细胞为基础治疗AD的方法是如何调节小胶质细胞的表型和功能。保存 Aβ 诱导的神经元细胞凋亡以及常驻小胶质细胞稳态功能的恢复 对于大脑功能的恢复至关重要。 该提案的目标是验证氙气 (Xe) 调节 AD 小鼠小胶质细胞的能力 模型和人类，这将导致新型 AD 治疗的发展。 Xe目前用于人类患者 作为麻醉剂和治疗脑损伤的神经保护剂。 Xe可穿透血脑屏障， 可以使其发挥有效的治疗作用。我们的初步数据表明，Xe 在急性和 AD 小鼠模型中 通过吸入传递调节大脑小胶质细胞并使其保持止血形式。在这个提案中 我们希望进一步验证 Xe 对 AD 小鼠模型和人类神经再生体内小胶质细胞的作用 小胶质细胞。我们将致力于实现以下目标： 目标 1：研究氙气治疗是否影响神经退行性疾病的表型和功能 APP-PS1 小鼠中的小胶质细胞。 目标 2：验证氙气治疗是否影响神经退行性人类的表型和功能 小胶质细胞。 根据这些工作的结果，我们将能够开发吸入系统和方案 AD治疗的治疗方法的实施。