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Modeling CNS dynamics in HIV infection and cannabinoids with forebrain organoids

用前脑类器官模拟 HIV 感染和大麻素中的中枢神经系统动力学

基本信息

批准号：
10656388
负责人：
Kimberly Christian
金额：
$ 69.52万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
2019-08-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10656388
关键词：
3-Dimensional Acute Adherence Adult Antiinflammatory Effect Astrocytes Autopsy Brain region Cannabinoids Cell Communication Cells Central Nervous System Central Nervous System Diseases Cerebral cortex Cerebrum Chronic Coculture Techniques Communicable Diseases Complement Data Set Development Disease Disease model Drug Addiction Drug abuse Early Diagnosis Early Intervention Electrophysiology (science)Exhibits Exogenous Factors Exposure to Genetic Genetic Transcription Glutamates Goals HIV HIV Infections HIV Seropositivity HIV-associated neurocognitive disorder Heterogeneity Human Immune system Immunologics Impaired cognition Impairment Individual Inflammatory Investigation Kinetics Macrophage Measures Mediating Medicine Microglia Modeling Molecular Profiling Morphology Neuroimmune Neurons Organoids Outcome Pathogenesis Pathology Patients Pharmaceutical Preparations Phenotype Physiological Play Population Predisposition Property Prosencephalon Quality of life Regimen Repression Resources Role Severities Somatic Cell Specificity Structure Symptoms Synapses System Technology Testing Therapeutic Time Tissues Tropism Viral Viral Load result Viral Proteins Viral reservoir Virulence Virus Replication Work animal data antiretroviral therapy behavioral impairment biological systems cell type cofactor combat comorbidity differentiation protocol directed differentiation dynamic system efficacy evaluation endocannabinoid signaling experimental study human disease improved induced pluripotent stem cell marijuana use motor impairment neural neuroinflammation neuron development neuropathology neurotoxic novel phytocannabinoid protein expression recruit response self organization single-cell RNA sequencing stem cell model three dimensional cell culture three dimensional structure three-dimensional modeling transcriptome transcriptome sequencing translational approach virus host interaction

项目摘要

PROJECT SUMMARY HIV-Associated Neurocognitive Disorder (HAND) persists in up to 50% of the HIV-positive population, often in spite of low or undetectable viral loads due to effective antiretroviral therapy (ART). Microglia are the resident macrophages in the central nervous system (CNS) and are thought to be a persistent reservoir of HIV in ART treated patients. Microglia secrete a panoply of factors that impact neuronal function and these secreted factors are altered during HIV infection of microglia. In addition to HIV virus-host interactions mediated by microglia, many exogenous factors can modify these interactions or directly impact the CNS itself, making it difficult to dissect the underlying causes of neural pathology leading to HAND. To establish a physiologically- relevant platform to investigate the dynamics of HIV infection in the context of ART and other co-factors, we will use human induced pluripotent stem cells to generate human microglia that we can co-culture with our well-characterized 3D model of the developing cerebral cortex. This integrated 3D cerebral organoid model will recapitulate many of the critical cell populations thought to contribute to HAND-related pathology including glutamatergic neurons, astrocytes, and microglia. We will evaluate the efficacy of the cerebral organoids to model HIV infections by measuring HIV replication kinetics and suppression, as well as HIV protein expression in different cell types (Aim 1). We will then measure the impact of HIV on neuronal development and function at several time points following acute exposure (Aim 2). We will perform morphological and electrophysiological analyses and RNA sequencing at both the single cell and population level to determine the cell type-specific transcriptional responses to HIV exposure. Finally, we will evaluate the impact of exogenous drugs on these measures of viral replication and neuronal function (Aim 3). As a proof-of-concept, we will test a preferred regimen of ART, as well as cannabinoids, both with and without HIV exposure to begin to dissect the impact of these common co-factors on cellular properties that may contribute to pathology underlying HAND. Successful completion of these experiments will result in a validated platform to model the dynamics of neuroinflammatory disorders using brain region-specific cerebral organoids integrated with human microglia.

项目总结