PATHOBIOLOGY OF BONE MARROW SUPPRESSION IN AIDS OR ARC

艾滋病或 ARC 骨髓抑制的病理学

• 批准号: 3242932
• 负责人: JOHN W ADAMSON
• 金额: $ 3.97万
• 依托单位: NEW YORK BLOOD CENTER
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-01-15 至 1991-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3242932
• 关键词: AIDS; AIDS /HIV test; AIDS therapy; HIV infections; blood disorder chemotherapy; cell adhesion; cell type; colony stimulating factor; erythropoietin; genetic manipulation; hematopoiesis; hematopoietic growth factor; hematopoietic stem cells; human subject; in situ hybridization; interleukin 1; interleukin 3; orotate; tissue /cell culture; zidovudine

The overall goals of the proposal are to characterize the hematopoietic defects associated with human immunodeficiency virus (HIV) infection in man. These defects have limited the ability to treat the acquired immunodeficiency syndrome (AIDS) with drugs such as azidothymidine (AZT). Specifically, we propose to determine the sensitivity to recombinant human hematopoietic growth factors of marrow progenitor cells obtained from normal subjects, patients who are HIV-antibody-positive but who do not yet have AIDS, and patients with AIDS or AIDS-related complex (ARC). As part of the study, we will establish adherent cell layers from marrow aspirates obtained from the various study groups and determine the ability of these layers to support hematopoiesis in vitro and to respond to inflammatory modulators such as interleukin-1 (IL-1) by the production of specific hematopoietic growth factors. In addition, using in situ hybridization techniques, we will determine if the stromal cells of the adherent marrow cells are infected by HIV. Similarly, we will determine whether hematopoietic progenitor cells are also productively infected by HIV. We will examine the effect of therapeutic drugs such as AZT and related compounds for their effect on hematopoietic progenitor cell growth in an attempt to explain the selectivity of the erythroid suppression exerted by AZT. We also will attempt to reverse the AZT effect through the addition of hematopoietic growth factors in vitro and by adding compounds such as orotic acid to culture to bypass the AZT-imposed cell defect. Finally, we will explore the mechanisms of interaction between AZT and acetominophen, a compound which enhances AZT toxicity. From such studies, we hope to understand the mechanisms underlying marrow suppression in AIDS and how AZT exacerbates marrow failure. Through such understanding may come strategies for reducing the frequency and severity of marrow failure in drug-treated patients.

该提案的总体目标是描述造血者的特征 与人类免疫缺陷病毒(HIV)感染相关的缺陷 天哪。这些缺陷限制了治疗获得者的能力 免疫缺陷综合征(AIDS)与药物，如叠氮胸苷(AZT)。 具体地说，我们建议确定对重组人 骨髓来源的造血祖细胞的造血细胞生长因子 正常受试者，HIV抗体阳性但尚未呈阳性的患者 有艾滋病、艾滋病患者或艾滋病相关情结(ARC)。作为一部分 在这项研究中，我们将从骨髓抽提物中建立贴壁细胞层 从不同的研究小组获得，并确定这些 体外支持造血和抗炎的蛋鸡 调节剂如白介素1(IL-1)通过产生特异性 造血生长因子。此外，使用原位杂交 技术，我们将确定贴壁骨髓的基质细胞 细胞被艾滋病毒感染。同样，我们将确定是否 造血祖细胞也会被艾滋病毒高效感染。我们 将检查治疗药物如AZT和相关药物的效果 化合物对小鼠造血祖细胞生长的影响 试图解释黄曲霉毒素对红细胞抑制的选择性 AZT。我们还将尝试通过添加来逆转AZT效应 体外的造血生长因子，并通过添加化合物，如 体外培养，绕过AZT造成的细胞缺陷。最后，我们 将探索AZT与扑热息痛相互作用的机制， 一种增强AZT毒性的化合物。通过这样的研究，我们希望 了解艾滋病患者骨髓抑制的机制以及AZT如何 会加重骨髓衰竭。通过这样的理解，可能会产生战略 在药物治疗中减少骨髓衰竭的频率和严重程度 病人。