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: 10455617
• 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 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10455617
• 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; Persons; Phagocytes; Phagocytosis; Phase; Phenotype; Phosphorylation; Plasma; 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; induced pluripotent stem cell; 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.

单核细胞天然免疫应答的破坏：对神经退行性变的贡献 摘要 阿尔茨海默病（Alzheimer's disease，AD）是阿尔茨海默病（Alzheimer's disease，AD）的主要病因，其特征是β-淀粉样蛋白（Aβ40和Aβ42）水平升高 痴呆症，在全球约12%的人口中流行。反过来，艾滋病毒相关的 神经认知障碍（HAND）在20-50%的艾滋病毒感染者（PWH）中流行1，2，尽管可以获得 联合抗逆转录病毒治疗（cART）。单核细胞募集到大脑促进巨噬细胞吞噬 清除Aβ斑块和恢复中枢神经系统（CNS）稳态（综述见3）。 然而，在HIV感染中，外周单核细胞浸润受损的血脑屏障（BBB）进入外周血。 CNS，引发炎症和神经元损伤4 -7。有趣的是，HAND患者表现出 血液8和大脑9 -12中的Aβ，尽管存在浸润的单核细胞。HIV劫持其靶细胞 通过削弱I型干扰素（IFN-1）信号传导来促进病毒复制13，14。在AD中，改变的IFN-1 应答减少了单核细胞向CNS的募集15。IFN-1信号传导损害胰岛素产生16- 18，胰岛素信号传导失调加剧Aβ斑块形成19，20。反过来，Aβ水平升高 导致胰岛素抵抗和认知能力下降21.在接受cART的HIV患者中，胰岛素抵抗患病率 与健康个体相比， 这表明代谢改变也可能有助于HAND 22，23的发展。 因此，Aβ代谢、胰岛素信号传导和认知障碍相互关联。由于其不同 病因学，AD病理学和HIV神经发病机制的共同机制还不清楚。 明白我假设单核细胞/巨噬细胞（Mφ）中受损的IFN-1信号转导改变了它们的功能。 表型和胰岛素受体（IR）代谢，导致HAND和AD的认知障碍 患者在这项研究中，我将确定Mφs IFN-1反应对认知能力下降的贡献，通过 以下目的：1）表征IFN-1信号传导和胰岛素受体生物学在单核细胞中的作用， AD和HAND患者的血液，按认知状态分层; 2）使用脑类器官模型，我将确定 单核细胞在HIV感染后是否具有神经保护作用或神经炎症作用，使用HIV阴性和 阳性受试者的单核细胞; 3）确定IFN-1受体调节对Mφs表型的影响， 和神经元功能障碍。这项研究的结果将揭示新的机制 参与神经退行性疾病中外周和CNS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，以开发有效的治疗方法， 手和AD的下降。拟议的培训计划是根据我在细胞生物学方面的专业知识量身定制的 和病毒免疫学，并通过新颖的3D脑类器官方法来扩展我的技能。的 多学科的辅导团队致力于提供职业指导，丰富我对新的知识 技术，并确保我在学术界转向独立，专门研究神经免疫学。