DEVELOPMENT OF A JANUS KINASE 3 (JAK3) INHIBITOR FOR USE IN RHESUS MACAQUES

用于恒河猴的 JANUS 激酶 3 (JAK3) 抑制剂的开发

• 批准号: 7958480
• 负责人: Louis J. Picker
• 金额: $ 8.86万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-04 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7958480
• 关键词: Acquired Immunodeficiency Syndrome; Cells; Computer Retrieval of Information on Scientific Projects Database; Data; Development; Family; Funding; Goals; Grant; Hand; Homeostasis; Homing; Immunologic Deficiency Syndromes; Infection; Institution; Interleukin 2 Receptor Gamma; Interleukin-15; Interleukin-2; Interleukin-4; Interleukin-7; Janus kinase 3; Macaca mulatta; Mediator of activation protein; Memory; Names; Pathogenesis; Pathogenicity; Play; Population; Primates; Production; Reagent; Research; Research Personnel; Resources; Rodent Model; Role; SIV; Signal Transduction; Source; T memory cell; T-Lymphocyte; Therapeutic; Tissues; United States National Institutes of Health; Viral; cytokine; in vivo; inhibitor/antagonist; interleukin-15 receptor; nonhuman primate; response; tool

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Our previous data place CD4+ central memory T cells and the mechanisms that maintain the homeostasis of this population and regulate its differentiation into tissue homing effector memory at the center of AIDS pathogenesis. In rodent models, the major regulators of memory T cell homeostasis are the common gamma chain cytokines IL-7 and IL-15, and we and others have demonstrated that these cytokines have analogous activities in non-human primates. The role of these cytokines in the SIV infection-associated CD4+ memory production response described above is unknown. It is very likely that either or both of these cytokines play a major part in this crucial response, and therefore counter the development of immunodeficiency. On the other hand, it is also possible that these pro-proliferative cytokines support or increase SIV pathogenicity by their ability to induce production of target (substrate) cells for viral replication. Understanding the role of common gamma chain cytokines IL-7 and IL-15 in maintaining and regulating T-cell populations during SIV infection will be necessary to better understand both pathogenic mechanisms and the potential for exploiting this regulatory axis for therapeutic benefit. IL-7 and IL-15 receptors share a common gamma chain (hence, the name "common gamma chain cytokine family"), and the use of Janus Kinase 3 (JAK3) as an intracellular signaling mediator downstream of this common gamma chain. Pharmacologic inhibition of JAK3 would inhibit the activities of both IL-7 and IL-15 (as well as other common gamma chain cytokines such as IL-2, IL-4 and IL-21, which have more specialized functions), and allow us to globally assess the overall role of these cytokines in AIDS pathogenesis. The goal of this project is to assess the potential of the JAK3 inhibitor JANEX-1 as a tool for in vivo inhibition of IL-7 and IL-15 activity in rhesus macaques, and to provide preliminary data demonstrating the utility of this reagent for assessment of the role of the common gamma chain cytokine family in SIV pathogenesis.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 我们之前的数据将 CD4+ 中央记忆 T 细胞以及维持该群体稳态并调节其分化为组织归巢效应记忆的机制置于艾滋病发病机制的中心。 在啮齿动物模型中，记忆 T 细胞稳态的主要调节因子是常见的 γ 链细胞因子 IL-7 和 IL-15，我们和其他人已经证明这些细胞因子在非人类灵长类动物中具有类似的活性。 这些细胞因子在上述 SIV 感染相关 CD4+ 记忆产生反应中的作用尚不清楚。 这些细胞因子中的一种或两种很可能在这一关键反应中发挥主要作用，从而对抗免疫缺陷的发展。 另一方面，这些促增殖细胞因子也有可能通过诱导产生病毒复制的靶（底物）细胞的能力来支持或增加 SIV 的致病性。 了解常见伽玛链细胞因子 IL-7 和 IL-15 在 SIV 感染期间维持和调节 T 细胞群中的作用对于更好地了解致病机制以及利用这一调节轴获得治疗益处的潜力是必要的。 IL-7 和 IL-15 受体共享共同的 γ 链（因此，名称为“共同γ链细胞因子家族”），并且使用 Janus 激酶 3 (JAK3) 作为该共同γ链下游的细胞内信号传导介质。 JAK3的药理学抑制将抑制IL-7和IL-15（以及其他常见的γ链细胞因子，如IL-2、IL-4和IL-21，它们具有更专门的功能）的活性，并使我们能够全面评估这些细胞因子在艾滋病发病机制中的总体作用。该项目的目标是评估 JAK3 抑制剂 JANEX-1 作为恒河猴体内抑制 IL-7 和 IL-15 活性的工具的潜力，并提供初步数据，证明该试剂在评估常见伽马链细胞因子家族在 SIV 发病机制中的作用方面的实用性。