权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Molecular mechanisms underlying HIV & Cocaine-mediated microglial activation: Targeting NLRP3 inflammasome

HIV的分子机制

基本信息

批准号：
10846423
负责人：
Shilpa J. Buch
金额：
$ 38.38万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-30 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10846423
关键词：
Acceleration Address Administrative Supplement Affect Aging Alzheimer&apos s Disease Amyloid Amyloid Proteins Amyloid beta-Protein Animals Anti-Retroviral Agents Archives Basal Ganglia Biological Markers Brain Brain region Cell Culture Techniques Chest Clinical Cocaine Cocaine Dependence DNA Methylation Data Deposition Disease Freezing Goals HIV HIV Infections HIV-associated neurocognitive disorder Hippocampus Immune Impaired cognition Individual Infection Inflammasome Lead Light Link Longevity Macaca Macaca mulatta Mediating Mediator Messenger RNA MicroRNAs Microglia Modeling Molecular Monkeys Neurocognitive Deficit Neurons Paraffin Pathogenesis Pathology Patients Peripheral Persons Phenotype Plasma Premature aging syndrome Prevalence Proteins Publishing Quality of life RNA Rat Transgene Recovery Reporting Residual state Rodent Role SIV Saline Sampling Signal Transduction Substance Use Disorder Symptoms Synapses Testing Untranslated RNA Viral Viral Proteins Viremia age related age related neurodegeneration aged aging brain amyloid pathology antiretroviral therapy biomarker identification brain tissue cocaine exposure cocaine use combinatorial comorbidity epidemiologic data extracellular vesicles frontal lobe glial activation human data improved male neurocognitive disorder neuroinflammation nonhuman primate novel parent grant peripheral blood senescence symptomatology tau Proteins tau-1

项目摘要

Summary: The parent grant (DA050545) focuses on assessing the role of microglial inflammasome NLRP3 in the context of neuroinflammation mediated by HIV and cocaine use. Since people living with HIV (PLWH) are now enjoying longer life-span, owing to effective combinatorial antiretrovirals, it is no surprise that there is an emerging surge of age-related comorbidities intersecting with the already existent HAND symptomatology in these individuals. In light of this, clinicians are seeing a rise in premature aging and Alzheimer’s-like phenotype in PLWH. Interestingly, in keeping with the clinical findings, studies from our lab have also demonstrated the accumulation of toxic amyloid deposits in the sections of brains from SIV-infected macaques as well as those from HAND patients with cocaine exposure (from NNTC) and, in the brains of HIV Transgenic rats exposed to cocaine (preliminary studies). Furthermore, in our recently reported cell culture study, we have also demonstrated that activated NLRP3 inflammasome generated from HIV Tat-activated microglia can shuttle to the bystander neurons via the extracellular vesicles (EVs), and unpublished data showed these EVs lead to upregulated expression of toxic amyloid proteins in the neurons. Taken together, we thus hypothesize that HIV Tat and cocaine-mediated activation of microglial NLRP3 (parent grant) could be shuttled through the microglial EVs to the recipient neurons to induce toxic amyloids and senescence mediators, which, in turn, could be detected as biomarkers in neuronal enriched EVs isolated from the plasma. While the focus of the parent grant is on understanding the role of activated NLRP3 inflammasome in the context of HIV Tat, and cocaine, the supplement aims to extend these studies to already available, archived plasma and brain samples from groups of SIV-infected rhesus macaques administered with/without cocaine for assessing the amyloid pathology and senescence phenotype in the brains of these animals and brain-derived neuronal EVs in the plasma. We will also correlate the expression of microglial NLRP3 in the brain with NLRP3 in plasma-enriched microglial EVs and expression levels of aging/AD cargos in the plasma-enriched neuronal EVs.

摘要：亲本拨款（DA050545）侧重于评估小胶质炎性体NLRP3在