nbInnate Immunity Responses In Monocytes: Contribution To Neurodegeneration

nb单核细胞的先天免疫反应：对神经退行性变的贡献

• 批准号: 10323605
• 负责人: Yisel M. Cantres-Rosario
• 金额: $ 11.58万
• 依托单位: UNIVERSITY OF PUERTO RICO MED SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10323605
• 关键词: 3-Dimensional; Abeta clearance; Academia; Affect; Alternative Splicing; Alzheimer' s Disease; Alzheimer' s Disease Pathway; Alzheimer' s disease brain; Alzheimer' s disease pathology; Alzheimer' s disease patient; Amyloid beta-42; Amyloid beta-Protein; Anti-Inflammatory Agents; Antiviral Therapy; Basic Science; Biology; Blood - brain barrier anatomy; Brain; CD14 gene; CRISPR/Cas technology; Cells; Cellular biology; Cerebrospinal Fluid; Characteristics; Clinical; Coculture Techniques; Cognition; Cognitive; Data; Dementia; Development; Ensure; Etiology; Exhibits; Exposure to; FCGR3B gene; Gene Expression; Goals; HIV; HIV Infections; HIV Seronegativity; HIV Seropositivity; HIV-associated neurocognitive disorder; Homeostasis; Human; Immune; Immune System Diseases; Immune response; Immune signaling; Immunity; Immunology; Impaired cognition; Impairment; In Vitro; Individual; Infection; Inflammation; Inflammatory; Insulin; Insulin Receptor; Insulin Resistance; Interferon Type I; Interferon-alpha; Interferon-beta; Interferons; Knowledge; Measures; Mediating; Mentors; Metabolic; Metabolism; Methodology; Modeling; Natural Immunity; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neuronal Dysfunction; Neurons; Neuropathogenesis; Neuropsychology; Organoids; Pathogenesis; Pathway interactions; Patients; Performance; Peripheral; Peripheral Blood Mononuclear Cell; Phagocytes; Phagocytosis; Phase; Phenotype; Phosphorylation; Plasma; Pluripotent Stem Cells; Population; Prevalence; Process; Reactive Oxygen Species; Receptor Signaling; Regulation; Research Personnel; Research Training; Role; Senile Plaques; Signal Pathway; Signal Transduction; Surface; Synapses; Technical Expertise; Techniques; Testing; Tissue Donors; Tissues; Training; Translational Research; Viral; Virus Replication; Vocational Guidance; abeta accumulation; antiretroviral therapy; brain tissue; cognitive function; cytokine; effective therapy; genetic variant; insulin receptor substrate 1 protein; insulin signaling; knock-down; macrophage; monocyte; multidisciplinary; neuroimmunology; neuroinflammation; novel; protein expression; receptor; receptor expression; recruit; response; restoration; skills; three dimensional cell culture; tool

Disruption of Innate Immunity Responses in Monocytes: Contribution to Neurodegeneration ABSTRACT Alzheimer’s disease (AD), characterized by elevated levels of β-amyloid (Aβ40 and Aβ42), is the leading cause of dementia, prevailing in approximately 12% of the population worldwide. In turn, HIV-associated neurocognitive disorders (HAND) prevail in 20-50% of people with HIV (PWH)1,2, despite the access to combined antiretroviral therapy (cART). Monocyte recruitment to the brain promotes macrophage phagocytic clearance of Aβ plaques and restoration of central nervous system (CNS) homeostasis (reviewed in3). However, in HIV infection, peripheral monocytes infiltrate the compromised blood brain barrier (BBB) into the CNS, triggering inflammation and neuronal damage4–7. Interestingly, HAND patients exhibit accumulation of Aβ in the blood8 and in the brain9–12, despite the presence of infiltrated monocytes. HIV hijacks its target cells to promote viral replication by impairing the interferon type I (IFN-1) signaling13,14. In AD, altered IFN-1 response decreases the recruitment of monocytes to the CNS15. IFN-1 signaling impairs insulin production16– 18, and dysregulated insulin signaling exacerbates Aβ plaque formation19,20. In turn, elevated levels of Aβ contribute to insulin resistance and cognitive decline21. In HIV patients on cART, insulin resistance prevalence is higher, compared to healthy individuals, which in turn is associated with worse neuropsychological performance, suggesting that metabolic alterations could also contribute to the development of HAND22,23. Thus, Aβ metabolism, insulin signaling, and cognitive impairment are interconnected. Due to their different etiologies, the shared mechanisms underlying AD pathology and HIV neuropathogenesis are not well understood. I hypothesize that impaired IFN-1 signaling in monocyte/macrophage (Mφs) alters their phenotype and insulin receptor (IR) metabolism, contributing to cognitive impairment in HAND and in AD patients. In this study, I will determine the contribution of the Mφs IFN-1 response to cognitive decline, through the following aims: 1) Characterization of IFN-1 signaling and insulin receptor biology in monocytes from the blood of AD and HAND patients, stratified by cognitive status; 2) using brain organoid models I will determine whether monocytes are neuroprotective or neuroinflammatory upon HIV infection, using HIV-negative and positive subjects’ monocytes; 3) I will determine the effect(s) of IFN-1 receptor modulation on Mφs phenotype, and neuronal dysfunction in vitro using brain organoids. Results from this study will uncover novel mechanisms involved in the crosstalk between the peripheral and CNS in neurodegenerative disorders. Further, our results will help identifying candidates and/or targets for the development of effective therapies against cognitive decline in HAND andAD. The proposed training plan is tailored to capitalize on my expertise in cellular biology and viral immunology, and to expand my skill set with novel 3D brain organoids methodologies. The multidisciplinary mentoring team is committed to provide career guidance, enrich my knowledge on new techniques, and ensure my transition to independence in academia, specializing in neuroimmunology.

单核细胞中先天免疫反应的破坏：对神经退行性的贡献 抽象的 阿尔茨海默氏病（AD），其特征是β-淀粉样蛋白水平升高（Aβ40和Aβ42）是主要原因 痴呆症，全世界约有12％的人口占普遍。反过来，艾滋病毒相关 在20-50％的艾滋病毒（PWH）1,2的人中，神经认知障碍（手）占上风 抗逆转录病毒疗法（CART）。单核细胞募集到大脑可促进巨噬细胞吞噬细胞 Aβ斑块的清除和中枢神经系统（CNS）稳态的恢复（综述为3）。 但是，在HIV感染中，周围单核细胞渗入受损的血脑屏障（BBB）中 中枢神经系统引发炎症和神经元损伤4-7。有趣的是，手动患者表现出 血液8和Brain9-12中的Aβ进行浸润的单核细胞的存在。 HIV劫持其目标细胞 通过损害I型干扰素（IFN-1）信号13,14来促进病毒复制。在AD中，IFN-1改变了 反应降低了单核细胞对CNS15的募集。 IFN-1信号传导会损害胰岛素的产生16- 18和失调的胰岛素信号传导加剧了Aβ斑块形成19,20。反过来，Aβ水平升高 有助于胰岛素抵抗和认知下降21。在购物车中的HIV患者中，胰岛素抵抗患病率 与健康的个体相比，它较高，而健康的个体又与较差的神经心理学有关 表现，表明代谢改变也可能有助于手动22,23。 Aβ代谢，胰岛素信号传导和认知障碍是相互联系的。由于他们的不同 病因，AD病理学和HIV神经病的基础的共同机制不是很好 理解齿。我假设单核细胞/巨噬细胞（MφS）中受损的IFN-1信号传导改变了它们 表型和胰岛素受体（IR）代谢，有助于手头和AD认知障碍 患者。在这项研究中，我将通过 以下目的：1）单核细胞中IFN-1信号传导和胰岛素受体生物学的表征 AD和手动患者的血液，按认知状况分层； 2）使用脑官型我将确定 单核细胞是在HIV感染后使用HIV阴性和 阳性受试者的单核细胞； 3）我将确定IFN-1受体调制对MφS表型的影响， 使用脑器官在体外进行神经元功能障碍。这项研究的结果将发现新的机制 在神经退行性疾病中参与周围和中枢神经系统之间的串扰。此外，我们的结果 将有助于确定候选人和/或目标，以开发有效的认知疗法 降低了安德。拟议的培训计划是为了利用我在细胞生物学方面的专业知识而量身定制的 和病毒免疫学，并通过新颖的3D脑器官方法来扩展我的技能。 多学科指导团队致力于提供职业指导，丰富我对新知识 技术，并确保我过渡到学术界的独立性，专门研究神经免疫学。