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Humanized Mice as a Tool to Monitor HIV Brain Reservoirs and Effects of Substance Abuse

人源化小鼠作为监测艾滋病毒脑库和药物滥用影响的工具

基本信息

批准号：
9321423
负责人：
Santhi Gorantla
金额：
$ 18.81万
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：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9321423
关键词：
Affect Aging Animal Model Animals Anti-Retroviral Agents Astrocytes Autopsy Blood Blood - brain barrier anatomy Blood Cells Bone Marrow Brain Brain Injuries Cell Communication Cells Central Nervous System Infections Chimera organism Chronic DNA Development Foundations Funding Goals HIV HIV Infections HIV-1 Hematopoietic Stem Cell Transplantation Hematopoietic stem cells Human Immune Immunity Infection Interleukins Investigation Life Liver Dysfunction Locales Lymphocyte Lymphoid Lymphoid Tissue Malabsorption Syndromes Mental Depression Microglia Modeling Monitor Mouse Strains Mus Nature Neuraxis Neurocognitive Deficit Neuroglia Neurons Neuropathogenesis Penetrance Peripheral Pharmaceutical Preparations Phase Prevention Research Resources Rest Rodent Model Role Substance abuse problem Substance of Abuse Testing Therapeutic Tissues Transgenic Organisms Viral Viral reservoir Virus Virus Diseases antiretroviral therapy astrocyte progenitor brain cell brain tissue cell type clinical effect clinically relevant cost cytokine efficacy testing exosome humanized mouse improved in vivo macrophage man mouse model nerve stem cell nervous system disorder nonhuman primate novel prevent public health relevance tool viral DNA viral RNA

项目摘要

DESCRIPTION: Combination antiretroviral therapy (cART), no matter how effective, cannot eliminate viral infection from its lymphoid and brain reservoirs. The blood-brain-barrier presents a substantive challenge as drug penetrance is often impeded. Moreover, the locale and extent of the viral brain reservoir has yet to be defined. This proposal seeks funds to establish a humanized mouse model to monitor formation of HIV reservoirs in hemato-lymphoid and CNS compartments, and in immune and non-immune cells (such as astrocytes). The focused use of mice carrying human blood and glia in the brain makes applicability to humans problematic. In turn, we are developing a resource that will generate improved animal models to study human glial cells interaction with peripheral immunity during HIV infection. Double humanized mice will be validated as a tool to study effects of substances of abuse on HIV CNS reservoir formation and eradication. Our goals to improve existing humanized mice models are as follows: R21 phase - 1) engraft human astrocytes and confirm their role in CNS HIV reservoir in vivo; and 2) enhance the development and function of human innate immune cells by transgenic expression of human IL-34 and assess cytokine effects on HIV-1 reservoir formation. R33 phase - 1) explore the effects of substances of abuse on formation of CNS reservoir and clearance by new antiretroviral approaches.

描述：联合抗逆转录病毒疗法（cART）无论多么有效，都无法消除其淋巴和脑储存库中的病毒感染。血脑屏障提出了实质性的挑战，因为药物渗透经常受到阻碍。此外，病毒脑库的位置和范围尚未确定。该提案寻求资金建立人源化小鼠模型，以监测血液淋巴和中枢神经系统区室以及免疫和非免疫细胞（例如星形胶质细胞）中艾滋病毒储存库的形成。重点使用携带人类血液和大脑神经胶质细胞的小鼠，这使得该技术在人类身上的适用性存在问题。反过来，我们正在开发一种资源，该资源将产生改进的动物模型，以研究艾滋病毒感染期间人类神经胶质细胞与外周免疫的相互作用。双人源化小鼠将被验证为研究滥用物质对艾滋病毒中枢神经系统储存库形成和根除影响的工具。我们改进现有人源化小鼠模型的目标如下： R21期 - 1）植入人星形胶质细胞并确认其在体内中枢神经系统HIV储存库中的作用； 2) 通过人 IL-34 的转基因表达增强人先天免疫细胞的发育和功能，并评估细胞因子对 HIV-1 储存库形成的影响。 R33 阶段 - 1) 通过新的抗逆转录病毒方法探索滥用物质对中枢神经系统储库形成和清除的影响。