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Stress Granule Formation in the Antiretroviral-Mediated Dysregulation of Oligodendrocyte Maturation in HIV-HAND

HIV-HAND 中抗逆转录病毒介导的少突胶质细胞成熟失调中的应激颗粒形成

基本信息

批准号：
10762118
负责人：
Eliana Vera von Krusenstiern
金额：
$ 4.77万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10762118
关键词：
Acceleration Acute Address Alzheimer&apos s Disease Amyotrophic Lateral Sclerosis Anti-Retroviral Agents Atrophic Autopsy Axon Behavioral Cell Death Cells Chronic stress Clinical Complex Cytoplasm Cytoplasmic Granules Data Drug Exposure Eukaryotic Cell Exhibits Exposure to Frontotemporal Dementia Functional disorder G3BP1 gene Genes HIV HIV-associated neurocognitive disorder Homeostasis Inhibition of Apoptosis Integrase Investigation Knock-out Lipids Measures Mediating Membrane Messenger RNA Myelin Nerve Degeneration Neurocognitive Neurocognitive Deficit Neurodegenerative Disorders Neurons Oligodendroglia Organelles Pathogenicity Pathologic Pathology Pathway interactions Patients Persons Pharmaceutical Preparations Pharmacotherapy Play Process Protein Biosynthesis Protein Kinase Proteins RNA-Binding Proteins Research Role Stress Symptoms Testing Translational Repression Translations United States Viral Viral Load result Work antiretroviral therapy arm attenuation biological adaptation to stress cell type experience experimental study frontotemporal lobar dementia amyotrophic lateral sclerosis improved outcome inhibitor insight motor deficit myelination nervous system disorder oligodendrocyte myelination preservation prevent retroviral-mediated stress granule stressor therapy design transcriptome treatment response white matter

项目摘要

PROJECT SUMMARY HIV-Associated Neurocognitive Disorder (HAND) is experienced by about half of people living with HIV (PWH), and presents as a spectrum of neurocognitive impairments. While the majority of PWH in the United States are virally suppressed or undetectable, the overall proportion of PWH with HAND symptoms has remained unchanged. One of the hallmarks of HAND is the atrophy of white matter, a pathology that persists in HAND patients treated with ART. The duration of ART treatment in PWH has been shown to correlate to the observed loss of white matter, leading to the concern that the drugs themselves are causing this pathology. The attenuation of white matter is associated with a loss of myelin, which in the CNS is produced by oligodendrocytes (OLs). Myelin is necessary for saltatory conduction and trophic support of axons and its loss may contribute to the clinical changes seen in HAND. Previous work from our lab has demonstrated that select ART drugs prevent the maturation of oligodendrocytes and myelination, though the mechanisms underlying these observations require additional investigation. We have further shown that treating maturing OLs with select ART drugs, such as Elvitegravir (EVG), activates the Integrated Stress Response (ISR), and inhibition of the ISR restores OL differentiation in the presence of EVG. The ISR is an adaptive pathway used to restore homeostasis in eukaryotic cells under stressful conditions, and is sometimes characterized by the formation of cytoplasmic stress granules (SGs), membraneless organelles thought to aid in the global inhibition of translation. Stress granules have not yet been extensively studied in oligodendrocytes, but research of other neurodegenerative diseases has found that their presence in neurons may cause acceleration of neurodegeneration. During chronic stress, SGs can become persistent, and the long-term aggregation of mRNAs and proteins can become pathological. There is strong evidence associating chronic SG accumulation in neurons with amyotrophic lateral sclerosis (ALS), Alzheimer’s, and frontotemporal dementia. Our lab has also observed SGs in post-mortem white matter of HIV+ patients with neurocognitive impairment. Furthermore, my preliminary data has shown that maturing OLs treated with EVG not only activate the ISR, but also form SGs that disappear with ISR inhibition. I hypothesize that during ARV drug treatment, stress granules sequester mRNAs needed for maturation of OLs via PERK activation of the ISR, and that these granules form to prevent cell death. I will test this hypothesis via three specific aims. AIM 1: I will determine if ARV Drug induced stress granules in OLs form via the PERK activated ISR. AIM 2: I will determine the contribution of SG formation to OL survival during ARV drug exposure. AIM 3: I will determine whether ARV-induced SGs in OLs sequester mRNAs needed for maturation and myelination. Since stress granules have not previously been characterized in oligodendrocytes, this work will not only provide insight into improving outcomes of ART treated PWH, but will also benefit research of other neurological diseases characterized by loss of white matter.

项目总结