Human Immune System Mouse Core

人体免疫系统鼠标核心

• 批准号: 10238750
• 负责人: Alejandro Benjamin Balazs
• 金额: $ 16.81万
• 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/10238750
• 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; Preparation; Price; Procedures; Research; Research Personnel; SIV; Sampling; Services; Source; System; T-Lymphocyte; 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; multiphoton imaging; nonhuman primate; nuclease; peripheral blood; programs; reconstitution; response; 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 人免疫系统鼠标核心（核心H） 人类免疫系统鼠标核心（HISMC）将为HU CFAR研究人员提供人源化的小鼠 研究人类免疫缺陷病毒（HIV）感染的模型。此外，HISMC将支持 早期的HU CFAR调查人员通过凭证计划访问这些模型。 尽管对HIV感染者和外周血细胞和体内研究的广泛相关研究和 组织活检，有关HIV发病机理和免疫力的基本问题仍未得到解答。能力 通过免疫系统的受控扰动研究艾滋病毒是人类受试者的限制，并且有限 获取人体组织样本使HIV复制和人类免疫回报的投资 艾滋病毒在血液以外的腔室中难以进行。因此，调查人员转向动物模型，但是 不幸的是，理想的艾滋病毒感染动物模型仍然难以捉摸。虽然猿猴免疫缺陷 猕猴的病毒（SIV）感染为逆转录病毒提供了许多至关重要的见解 发病机理和免疫学，猕猴对SIV和人类的免疫反应存在差异 对艾滋病毒的反应。此外，与NHP研究相关的费用限制了对该模型的访问。解决 这些局限性，具有人类免疫细胞的嵌合“人性化小鼠”。 HU CFAR HISMC生成完整的人源性小鼠模型：人类外周血白细胞（HU-PBL） 小鼠，造血干细胞（HU-HSC）小鼠和骨髓 - 肝硫肌（BLT）小鼠。支持研究 HISMC证明，这些小鼠概括了人类艾滋病毒感染的多个方面 例如，阴道爆发后感染的“日食”阶段的存在；类似的部署 感染后外周血和粘膜组织中的CD4+ T细胞；并支持高级体内成像 通过多光子内感染显微镜和生物发光成像，HIV感染的感染。他们还为 研究治疗的影响，例如ART或抗体，对HIV。 在即将到来的资金期间，HISMC将提供对这些人源化老鼠的访问权限 MGH/Partners Healthcare Core。因此，老鼠及其产生涉及的所有费用 实验操作包括在服务价格中。 CFAR支持将完全是 针对凭证计划，以支持早期职业生涯的访问hu CFAR调查人员参与这些 服务。这些优惠券将涵盖与人性化小鼠实验有关的成本，并将仅限于早期 职业生涯CFAR调查人员没有其他来源的人源化老鼠研究资金的资金。