CHEMOKINE RECEPTORS AND ITP AND HIV THROMBOCYTOPE

趋化因子受体、ITP 和 HIV 血小板

• 批准号: 6527522
• 负责人: Shahin Rafii
• 金额: $ 33.41万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 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/6527522
• 关键词: HIV envelope protein gp120; HIV infections; autoimmune disorder; bone marrow; cell adhesion; cell adhesion molecules; cell communication molecule; cell migration; chemokine; clinical research; cytokine receptors; growth factor receptors; hematopoietic growth factor; human subject; laboratory mouse; megakaryocytes; selectins; thrombocytopenia; transfection; vascular endothelium

DESCRIPTION (Adapted from applicant's abstract) Thrombocytopenia is one of the life threatening hematologic disorders that may occur as a result of autoimmune process or during the asymptomatic and clinical stage of HIV-1 infection. It is hypothesized that disruption of chemokine network, and adhesive interactions between megakaryocytes (MKs) and bone marrow endothelium (BMEC) as it may occur during HIV infection, plays a seminal role in the failure of MK transmigration and platelet release. The exact mechanism and site of platelet formation is not well defined. Studies have shown that transmigration of MK through BMEC, may be critical for platelet formation. The investigators have discovered that mature polypoid MKs express the chemokine receptor (HIV co-receptor): CXCR4. Stromal Derived Factor 1 (SDF1) which is the ligand for the CXCR4, promotes transmigration of MKs through BMEC monolayers. They have also identified a novel endothelial cell derived factor (ECDF1) that selectively induce migration of MKs through BMEC. Transendothelial migration of MKs in response to SDF1 or ECDF1 enhances formation of functional platelets. Interaction of migration MK with adhesion molecules expressed on MBEC such as E-selectin and PECAM is critical for MK migration and optimal platelet formation. They have also discovered that HIV can inject MKs through CXCR receptor, interfering with transendothelial migration of Mks, and platelet release. In this proposal they plan to 1) Define the mechanism whereby SDF1 and ECDF1 modulate adhesion molecule adhesion molecule expression of MK and BMEC cells. 2) Characterize cellular signaling pathways such as apoptotic pathways that may be induced by transmigration of Mks. 3) Take advantage of the availability of MK and BMEC derived from E-selectin knockout mice to study the role of these factors in regulation of CXCR expression. Both MKs and BMEC express CD4 and CXCR4, and are therefore susceptible to HIV infection. Therefore, it is planned to define the mechanism whereby HIV infection of either Mks and BMEC may influence chemokine receptor, and adhesion molecule expression resulting in dysfunction or platelet formation. Whether HIV-1 gp120 or other factors including megakaryopoietins that interact with CXCR4 may also influence platelet formation will also be explored. They plan to over-express CXCR4 and SDF1 within the milieu of marrow microenvironment by adenoviral vectors to explore the possibility of augmenting platelet production. This project should lead to the definition of the role of chemokines and adhesion molecules expressed by BMEC that regulate platelet production. Identification of chemokine receptors that may regulate platelet production may elucidate pathogenesis of thrombocytopenia in HIV or other thrombocytopenic states and suggest potential pharmacological interventions. Modulation of chemokine receptors expression by adenoviral vectors overexpressing SDF1, ECDF1 or their receptors may allow for developing therapies to ameliorate thrombocytopenia in vivo.

描述 （改编自申请人的摘要）血小板减少症是生活之一 威胁由于自身免疫而可能发生的血液学疾病 HIV-1感染的过程或无症状和临床阶段。 假设趋化因子网络和粘合剂的破坏 巨核细胞（MK）和骨髓内皮之间的相互作用 （BMEC）可能在HIV感染期间发生，在 MK转移和血小板释放的故障。确切的机制和 血小板形成的部位不是很好的定义。研究表明 MK通过BMEC的迁移对于血小板形成至关重要。 调查人员发现成熟的息肉MK表达 趋化因子受体（HIV共受体）：CXCR4。基质衍生因子1 （SDF1）是CXCR4的配体，促进MKS的移民 通过BMEC单层。他们还确定了一个新颖的内皮 细胞得出的因子（ECDF1）选择性诱导MK的迁移 通过BMEC。 MKS对SDF1的跨内皮迁移或 ECDF1增强了功能血小板的形成。迁移的相互作用 MK具有在MBEC上表达的粘附分子，例如E-选择蛋白和PECAM 对于MK迁移和最佳血小板形成至关重要。他们有 还发现HIV可以通过CXCR受体注入MK，干扰 MK的跨内皮迁移和血小板释放。在这个 提案他们计划1）定义SDF1和ECDF1的机制 调节MK和BMEC的粘附分子粘附分子表达 细胞。 2）表征细胞信号通路，例如凋亡 MKS迁移可能引起的途径。 3）利用优势 从E-选择蛋白敲除小鼠衍生的MK和BMEC的可用性 研究这些因素在调节CXCR表达中的作用。两个都 MKS和BMEC Express CD4和CXCR4，因此容易受到HIV的影响 感染。因此，计划定义艾滋病毒的机制 MK和BMEC的感染可能会影响趋化因子受体，并且 粘附分子表达导致功能障碍或血小板 形成。 HIV-1 GP120还是其他因素 与CXCR4相互作用的巨核素也可能影响血小板 编队也将探讨。他们计划过表达CXCR4和SDF1 在腺病毒载体的骨髓微环境环境中 探索增加血小板产生的可能性。这个项目 应该导致趋化因子和粘附作用的定义 由BMEC表达的分子调节血小板的产生。 鉴定可能调节血小板的趋化因子受体 生产可能阐明HIV或其他HIV中血小板减少症的发病机理 血小板减少态并提出潜在的药理 干预措施。腺病毒调节趋化因子受体表达 过表达SDF1，ECDF1或其受体的向量可能允许 开发在体内改善血小板减少症的疗法。