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Research Support Core B: Primary Cell, Biomimetic, and iPSC-derived Cell Models

研究支持核心 B：原代细胞、仿生和 iPSC 衍生细胞模型

基本信息

批准号：
10304584
负责人：
JONATHAN KARN
金额：
$ 73.12万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-15 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10304584
关键词：
Behavior Biological Biological Assay Biological Models Biomimetics Blood Cells Blood Circulation Brain CD4 Positive T Lymphocytes CRISPR/Cas technology Cannabis Cell Line Cell model Cells Cerebrum Clinical Clinical Trials Cocaine Coculture Techniques Collaborations Color Complex DNA Drug Targeting Drug usage Endothelial Cells Endothelium Epithelial Cells Gap Junctions Genes Goals Guide RNA HIV HIV Genome HIV Infections Immune system In Vitro Individual Induced pluripotent stem cell derived neurons Inflammation Innate Immune System Institution Intestines Measures Methamphetamine Methods Microbiology Microglia Migration Assay Modeling Modification Molecular Mucous Membrane Neurodegenerative Disorders Neurons Nucleic Acids Opioid Organ Organoids Pathogenesis Patients Peripheral Persons Pharmaceutical Preparations Primary Cell Cultures Proteomics RNA Research Research Personnel Research Support Ribonucleoproteins Sampling Services Small Intestines Stimulus Study models Substance Use Disorder System T memory cell T-Lymphocyte Techniques Technology Tissue Sample Tissues Training Vascular Permeabilities Viral reservoir Virus antiretroviral therapy base brain endothelial cell cell transformation cell type digital droplet sequencing drug of abuse genome editing human model immunoregulation in vivo induced pluripotent stem cell innovation intestinal epithelium latent HIV reservoir metabolomics monolayer nervous system disorder new technology novel phenotypic biomarker response single-cell RNA sequencing stem cell technology substance use tool transcriptomics viral DNA viral RNA viral detection

项目摘要

Project Summary - Primary Cell, Biomimetics, and iPSC-derived Cellular Models Core B Understanding the mechanism(s) by which cocaine, methamphetamine, cannabis, and opioids amplify the damage of HIV latency is a central goal of the CWRU Center for Excellence on the Impact of Substance Use on HIV. Our understanding of HIV latency and persistence has been complicated by the small numbers of latently infected cells found in the circulation, the difficulty of obtaining comprehensive sets of tissue samples from patients, the lack of known phenotypic markers that can distinguish latently infected cells from uninfected ones, and limited information about the behavior of tissue reservoirs in vivo. Core B will provide both ex vivo primary cell models (Aim 1) and highly sensitive nucleic acid-based assays to measure the impact of substance use on the HIV reservoir (Aim 2) in clinical samples. A key unresolved issue is how each individual drug modulates the latent HIV reservoir in multiple cell types and tissues. The Primary Cell, Biomimetic, and iPSC-derived Cell Models Core B team will provide and develop for Center investigators innovative and highly informative cellular and biomimetic models for the three main organ targets of drug use and HIV – the brain, gut, and the immune system. Organoids derived from tissue explants and induced pluripotent stem cells (iPSC) will be used to mimic the tissue microenvironment and extend the range of assays beyond what can be achieved using single cell ex vivo models. The models offered by Core B will be used throughout the Center of Excellence to evaluate the impact of drug use on HIV latency and will also be established ex vivo with samples derived from persons with Substance Use Disorder and HIV on anti-retroviral therapy. These models will each reflect the diversity of molecular mechanisms governing the response to drug use and HIV latency in CD4 T cells from the periphery, mucosal T cells from the gut, and microglial, neuronal, and microvascular endothelial cells from the CNS and will also provide unique opportunities to contrast the effects of substance use in vivo with direct cell biological analyses ex vivo. Importantly, the Core B team will continue to develop new assays and methods to study the impact of substance use on the mechanisms of HIV persistence and latency. In particular, this effort includes (a) developing single cell RNA induction assays, (b) modeling the TFH compartment, and (c) advancing iPSC-derived cerebral organoids to study drug use and HIV latency in the CNS. Thus, Core B, in collaboration with the molecular services in Core C, will provide access to novel technologies for evaluating the cellular, proteomic, microbiological, metabolomic, and transcriptomic changes associated with substance use and their impact on HIV reservoirs in patient samples available in Core D and to primary cell cultures and tools to manipulate cells that would not otherwise be available to Substance Use researchers at our institutions and nationwide.

原代细胞，仿生学和ipsc衍生的细胞模型