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.

单核细胞先天免疫反应的破坏：对神经退行性变的贡献