CELLULAR AND MOLECULAR BASIS OF HIV BASED THROMBOCYTOPEN

基于 HIV 的血小板平的细胞和分子基础

• 批准号: 6056567
• 负责人: Mariusz Z Ratajczak
• 金额: $ 17.45万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6056567
• 关键词: AIDS; HIV infections; NOD mouse; RNase protection assay; SCID mouse; SDS polyacrylamide gel electrophoresis; apoptosis; cellular pathology; cytokine receptors; electron microscopy; enzyme linked immunosorbent assay; flow cytometry; human immunodeficiency virus 1; human immunodeficiency virus 2; human tissue; megakaryocytes; mixed tissue /cell culture; molecular pathology; northern blottings; plateletpheresis; polymerase chain reaction; thin layer chromatography; thrombocytopenia; thrombopoiesis; thrombopoietic factor; virus protein

DESCRIPTION (Adapted from applicant's abstract) Autoimmune mechanisms are known to play a role in the thrombocytopenia observed in individuals infected with the human immunodeficiency virus (HIV) who suffer from the Acquired Immune Deficiency Syndrome (AIDS). However, immunologic mechanisms alone are unlikely to account for all aspects of the pathogenesis of thrombocytopenia seen in AIDS. Among these other mechanisms are possible direct effects of the HIV, or its associated proteins, on the development of megakaryopoietic progenitors in the bone marrow, or the ability of these cells to carry out thrombopoiesis, the process of platelet production. It is also possible that these effects may be brought about indirectly by effects of the virus, or viral proteins, on marrow stromal and accessory cells supportive of megakaryocytopoiesis. To investigate these issues, The applicants propose the following four specific aims: I. Determine the effect of HIV infection on megakaryopoiesis and platelet formation. They will infect human megakaryocytic cells at various stages of development with HIV-1 and HIV-2 viruses and examine the ability of these cells to differentiate into mature megakaryocytes and form platelets. If these processes are impaired, they will determine the mechanism(s) involved. II. Characterize the chemokine receptors on megakaryocytes and the influence of their corresponding ligands on megakaryopoiesis. They will characterize the chemokine receptors displayed on uninfected and infected megakaryocytes, and study the influence of these receptor-ligand pairs on the developmental biology of these cells. These studies will shed light on the function of these chemokines during megakaryocytopoiesis and thrombopoiesis. III. Investigate the role of HIV proteins and HIV-induced cytokines on thrombocytopenia. They will evaluate the influence of viral proteins and inflammatory cytokines elaborated during infection by accessory cells on the developmental biology of megakaryopoietic precursors and mature cells. IV. Develop strategies for preventing HIV-induced thrombocytopenia. Inhibitory mutants of chemokines have already been developed and shown to prevent HIV infection. Based on findings in the first 3 specific aims, they plan to test blocking chemokines and monoclonal antibodies, and blocking of various cytokines on megakaryopoiesis both ex vivo and in NOD/SCID (non obese diabetic/severe combined immunodeficiency) mice/human hematopoietic chimeras. In toto, the studies proposed in this grant will increase the knowledge about pathogenesis of AIDS associated thrombocytopenia and may lead to development of new strategies for its treatment of prevention. (End of Abstract)

描述 （根据申请人的摘要改编）自身免疫机制可以发挥作用 在感染的个体中观察到的血小板减少症中的作用 患有获得的免疫的人类免疫缺陷病毒（HIV） 缺陷综合征（AIDS）。 但是，仅免疫机制就是 不可能说明血小板减少症的发病机理的各个方面 在艾滋病中看到。 在这些其他机制中，可能是可能的直接影响 艾滋病毒或其相关蛋白质有关巨型巨质的蛋白质 骨髓中的祖细胞，或这些细胞进行的能力 血小板，血小板产生过程。 也可能 这些影响可能通过病毒的影响而间接带来 或病毒蛋白，在骨髓基质和辅助细胞上支持 巨核细胞质。 为了调查这些问题，申请人建议 以下四个特定目标：I。确定HIV感染的影响 在巨型杂质和血小板形成上。 他们会感染人类 HIV-1和HIV-2发育的各个阶段的巨核细胞细胞 病毒并检查这些细胞分化为成熟的能力 巨核细胞并形成血小板。 如果这些过程受到损害，他们 将确定所涉及的机制。 ii。 表征趋化因子 巨核细胞上的受体及其相应配体的影响 在巨型摩毛虫上。 他们将表征趋化因子受体 显示在未感染和感染的巨核细胞上，并研究影响 这些受体配体对这些细胞的发育生物学对。 这些研究将阐明这些趋化因子的功能 巨核细胞增多和血小板。 iii。 调查艾滋病毒的作用 蛋白质和HIV诱导的细胞因子在血小板减少症上。 他们将评估 病毒蛋白和炎性细胞因子在期间阐述的影响 辅助细胞感染的发育生物学 巨核前体和成熟细胞。 iv。 制定策略 预防HIV诱导的血小板减少症。 趋化因子的抑制突变体 已经开发并显示以防止艾滋病毒感染。 基于 在前3个特定目的中，他们计划测试阻断趋化因子 和单克隆抗体，以及在各种细胞因子上阻塞 巨核菌都在体内和点头/scID（非肥胖糖尿病/重度） 联合免疫缺陷）小鼠/人类造血嵌合体。 在Toto中 该赠款中提出的研究将增加有关 艾滋病的发病机理相关的血小板减少症，可能导致发育 预防治疗的新策略。 （抽象的结尾）