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.

I期应用 （STTR计划PAS-19-317） “ Xenon气体处理以调节神经退行性疾病中的小胶质细胞” 抽象的 阿尔茨海默氏病（AD）是最普遍的神经退行性疾病。新兴证据表明 大脑免疫学的稳态失调，尤其是小胶质细胞策划的稳态失调，发挥了 在疾病的发作和进展中的重要作用。小胶质细胞功能保持在健康的大脑中 并且在AD大脑中病原体失调。明显的遗传危险因素APOE参与 小胶质功能。我们最近确定了稳态小胶质细胞的独特分子签名，并具有 开发了健壮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 在调节与神经变性和小胶质细胞相关的新小胶质细胞子集中的apoe信号 我们称为MGND的人类广告大脑中的神经质AB-Plaques。主要问题与 基于小胶质细胞的方法治疗AD的方法是如何调节小胶质细胞表型和功能。保存 来自Aβ诱导凋亡的神经元细胞以及居民小胶质稳态功能的恢复是 对脑功能的恢复至关重要。 该提案的目的是验证氙气（XE）气体调节AD鼠标中的小胶质细胞的能力 模型和人类，这将导致新的AD治疗的发展。 XE目前用于人类患者 作为麻醉和作为脑损伤治疗的神经保护剂。 XE穿透了血脑屏障， 可以使其有效的疗法。我们在XE的急性和AD鼠标模型中证明了我们的初步数据 通过吸入传递可调节脑小胶质细胞并以止血形式保存。在此提案中 我们想进一步验证AD小鼠模型中的小胶质细胞和神经生成人类的XE作用 小胶质细胞。我们将在以下目的中解决我们的假设： 目标1：研究XE-GAS治疗是否影响神经退行性的表型和功能 App-PS1小鼠中的小胶质细胞。 目标2：验证XE-GAS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协议 实施用于AD治疗的治疗方法。