Human Immune System Mouse Core

人体免疫系统鼠标核心

基本信息

批准号：
10675451
负责人：
Alejandro Benjamin Balazs
金额：
$ 53.96万
依托单位：
HARVARD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-07-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10675451
关键词：
Acquired Immunodeficiency Syndrome Address Adult Animal Model Animals Antibodies Autologous BLT mice Biopsy Blood Blood Cells Blood specimen CD4 Positive T Lymphocytes CRISPR/Cas technology Cells Chlamydia trachomatis Containment Correlative Study Data Development Doctor of Philosophy Education Engraftment Evolution Fetal Liver Funding Future Generations Grant HIV HIV Infections HIV/TB Healthcare Hematopoietic Hematopoietic stem cells Human Immune Immune response Immune system Immunity Immunization Immunoglobulins Immunologic Deficiency Syndromes Infection Investigation Knock-in Mouse Leukocytes Light Liver Macaca Macaca mulatta Manuscripts Mediating Modeling Mucous Membrane Mus Operative Surgical Procedures Pathogenesis Patients Persons Phase Predisposition Preparation Price Procedures Productivity Research Research Personnel SIV Sampling Services Source System T-Cell Activation Therapeutic Thymic Tissue Tissue Sample Tissues Umbilical Cord Blood United States National Institutes of Health Universities Vaccines Virus Diseases bioluminescence imaging career co-infection cost experimental study human fetal thymus human subject human tissue humanized mouse implantation improved in vivo in vivo imaging insight intravital microscopy member microscopic imaging mouse model multi-photon nonhuman primate nuclease peripheral blood programs reconstitution response simian human immunodeficiency virus success treatment effect voucher

项目摘要

PROJECT SUMMARY/ABSTRACT Human Immune System Mouse Core (Core H) The Human Immune System Mouse Core (HISMC) will provide HU CFAR investigators with humanized mouse models in which to study human immunodeficiency virus (HIV) infection. In addition, the HISMC will support early career HU CFAR investigators to access these models through a Voucher program. Despite extensive correlative studies of HIV-infected persons and ex vivo studies of peripheral blood cells and tissue biopsies, fundamental questions about HIV pathogenesis and immunity remain unanswered. The ability to study HIV through controlled perturbations of the immune system is limited in human subjects, and limited access to human tissue samples makes the investigation of HIV replication and human immune responses to HIV difficult in compartments other than the blood. Investigators have therefore turned to animal models, but unfortunately an ideal animal model of HIV infection has remained elusive. Although simian immunodeficiency virus (SIV) infection of rhesus macaques has provided many critically important insights into retroviral pathogenesis and immunity, there are differences inherent in macaque immune responses to SIV and human responses to HIV. Moreover, expenses associated with NHP studies limit access to this model. To address these limitations, chimeric “humanized mice” with human immune cells have been generated. The HU CFAR HISMC generates complementary humanized mouse models: human peripheral blood leukocytes (hu-PBL) mice, hematopoietic stem cells (hu-HSC) mice and bone marrow-liver-thymus (BLT) mice. Studies supported by the HISMC have demonstrated that these mice recapitulate multiple aspects of HIV infection in humans such as the presence of an “eclipse phase” of infection following intravaginal challenge; similar depletion of CD4+ T cell in peripheral blood and mucosal tissues following infection; and support advanced in vivo imaging of HIV infection by multiphoton-intravital microscopy and bioluminescence imaging. They also offer a model to study the effect of treatment, such as ART or antibodies, against HIV. In the coming funding period, the HISMC will provide access to these models of humanized mice as a new MGH/Partners Healthcare Core. As such, all costs involved in the generation of the mice and their experimental manipulations are included in the price of the services. The CFAR support will be entirely directed towards a voucher program to support access of early career HU CFAR investigators to these services. These vouchers will cover costs related to humanized mice experiments and will be restricted to early career HU CFAR investigators who have no grant funding for humanized mouse studies from other sources.

项目概要/摘要人体免疫系统鼠标核心 (Core H) 人类免疫系统小鼠核心 (HISMC) 将为 HU CFAR 研究人员提供人源化小鼠此外，HISMC 将支持研究人类免疫缺陷病毒 (HIV) 感染的模型。早期职业 HU CFAR 研究人员通过优惠券计划访问这些模型。尽管对 HIV 感染者进行了广泛的相关研究，并对外周血细胞和尽管组织活检尚未解决，但有关艾滋病毒发病机制和免疫的基本问题仍未得到解答。通过控制免疫系统的扰动来研究艾滋病毒在人类受试者中是有限的，并且有限获取人体组织样本可以研究 HIV 复制和人体免疫反应因此，研究人员转向动物模型，但在血液以外的其他部位很难检测到艾滋病毒。不幸的是，尽管猿猴免疫缺陷，但理想的艾滋病毒感染动物模型仍然难以捉摸。恒河猴病毒（SIV）感染为逆转录病毒提供了许多至关重要的见解发病机制和免疫方面，猕猴对 SIV 的免疫反应与人类存在固有的差异此外，与 NHP 研究相关的费用限制了该模型的使用。这些限制，与人类免疫细胞嵌合的“人源化小鼠”已经产生。 HISMC 生成互补的人源化小鼠模型：人外周血白细胞 (hu-PBL) 小鼠、造血干细胞 (hu-HSC) 小鼠和骨髓-肝-胸腺 (BLT) 小鼠的研究支持。 HISMC 的研究表明，这些小鼠重现了人类 HIV 感染的多个方面例如在阴道内攻击后出现类似的感染“衰弱期”；感染后外周血和粘膜组织中的 CD4+ T 细胞支持先进的体内成像；他们还提供了一个模型来通过多光子活体显微镜和生物发光成像来检测艾滋病毒感染。研究抗艾滋病毒治疗（例如 ART 或抗体）的效果。在接下来的资助期内，HISMC 将提供这些人源化小鼠模型作为新的研究对象。 MGH/Partners Healthcare Core 因此，所有成本都涉及小鼠及其繁殖。 CFAR 支持将完全包含在服务价格中。针对代金券计划，以支持早期职业 HU CFAR 调查员获得这些这些优惠券将涵盖与人源化小鼠实验相关的费用，并且仅限于早期。职业 HU CFAR 研究人员，没有其他来源的人源化小鼠研究资助。