Human Immune System Mouse Core

人体免疫系统鼠标核心

• 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
• 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

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.

项目摘要/摘要 人类免疫系统小鼠核心(核心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 研究人类免疫缺陷病毒(HIV)感染的模型。此外，HISMC将支持 早期职业生涯胡CFAR调查人员通过代金券计划访问这些模型。 尽管对艾滋病毒感染者进行了广泛的相关研究，并对外周血细胞和 组织活检、关于艾滋病毒发病机制和免疫的基本问题仍未得到回答。一种能力 通过受控的免疫系统扰动来研究艾滋病毒在人类受试者中是有限的，而且有限 获取人体组织样本使艾滋病毒复制和人类免疫反应的研究成为可能 艾滋病毒很难在血液以外的隔室中传播。因此，研究人员转向了动物模型，但 不幸的是，理想的艾滋病毒感染动物模型仍然难以找到。尽管猿猴免疫缺陷 猕猴的病毒(SIV)感染为研究逆转录病毒提供了许多至关重要的见解 致病机制和免疫，猕猴对SIV和人类的免疫反应存在固有的差异 对艾滋病毒的反应。此外，与NHP研究相关的费用限制了对这一模式的使用。致信地址 在这些局限性下，嵌合的“人源化小鼠”已经与人类免疫细胞产生了。HU CFAR HISMC建立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-肝脏-胸腺(BLT)小鼠。支持的研究 HISMC的研究表明，这些小鼠概括了人类感染艾滋病毒的多个方面 例如，在阴道内挑战后出现感染的“月食相”；类似的耗竭 感染后外周血和粘膜组织中的CD4+T细胞；并支持先进的体内成像 通过多光子活体显微镜和生物发光成像检测艾滋病毒感染。他们还提供了一个模型来 研究抗艾滋病毒治疗的效果，如抗逆转录病毒药物或抗体。 在接下来的资助期，HISMC将提供这些人源化小鼠模型作为一种新的 MGH/合作伙伴医疗保健核心。因此，小鼠及其后代所涉及的所有成本 服务的价格中包括了实验性的操纵。CFAR的支持将完全是 针对凭证计划，以支持早期职业生涯HU CFAR调查人员访问这些 服务。这些代金券将包括与人源化小鼠实验相关的费用，并将仅限于早期 职业胡CFAR研究人员，他们没有从其他来源获得人源化老鼠研究的赠款资金。