ENDOTHELIAL CELL IN PATHOGENESIS OF HIV LINKED TTP

内皮细胞在 HIV 相关 TTP 发病机制中的作用

• 批准号: 2750533
• 负责人: JEFFREY C LAURENCE
• 金额: $ 31.2万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-08-01 至 2000-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2750533
• 关键词: CD95 molecule; HIV infections; affinity chromatography; antiantibody; apoptosis; crosslink; cytokine; enzyme inhibitors; human tissue; immunopharmacology; ligands; monocyte; pathology; platelet aggregation; polymerase chain reaction; protein kinase; protein tyrosine phosphatase; reagent /indicator; receptor expression; thrombocytopenic purpura; thrombosis; tissue /cell culture; tumor necrosis factor alpha; vascular endothelium

DESCRIPTION: (Adapted from applicant's abstract) The hypothesis for this proposal is that plasma factors, including tumor necrosis factor (TNF)- alpha and anti-CD36 antibodies, play a major etiologic role in TTP associated with HIV infection through induction of endothelial cell (EC) apoptosis. This is based upon four preliminary observations: the ability of these sera to induce apoptosis in microvascular but not large vessel EC; the upregulation of TNF-alpha in a small subset of HIV+ patients to concentrations associated with programmed cell death of EC in vitro; the relationship of CD36 cross-linking to activation of protein phosphokinases implicated in induction of apoptosis; and the expression of one membrane molecule critical to apoptosis, Fas, on subsets of microvascular EC, and its upregulation by TTP sera. We will examine the immunobiology of human microvascular EC in terms of interactions with TTP sera and plasma from HIV+ and HIV seronegative individuals, TNF-alpha, anti-CD36 isolated from patients with TTP, and HIV-infected monocytes. Specificity will be sought in parallel experiments with large vessel EC, which are not affected by the pathologic process of TTP. This proposal attempts to unify and interrelate several distinct observations characteristic of TTP: development of platelet thromboses limited to the microvasculature, accompanied by EC proliferation, damage, and exposure of subendothelial layers, all in the absence of an inflammatory response. Based upon the likelihood that both Fas/Fas ligand interactions and CD36 cross- linking are facilitated by TTP plasma factors, leading to microvascular EC activation, protein kinase induction, and EC apoptosis as well as platelet aggregation, we will examine the possibility of developing specific treatments for TTP based upon protein kinase inhibitors and CD36 peptides. (End of Abstract)

描述：（改编自申请人的摘要）对此的假设 建议是血浆因子，包括肿瘤坏死因子（TNF）- α 和抗 CD36 抗体在 TTP 中起主要病因作用 通过诱导内皮细胞 (EC) 与 HIV 感染相关 细胞凋亡。这是基于四项初步观察： 这些血清能够诱导微血管细胞凋亡，但不能诱导大血管细胞凋亡 容器 EC；一小部分 HIV+ 患者中 TNF-α 的上调 患者达到与 EC 程序性细胞死亡相关的浓度 体外; CD36交联与蛋白质激活的关系 参与细胞凋亡诱导的磷酸激酶；和表达 一种对细胞凋亡至关重要的膜分子 Fas，位于 微血管 EC 及其 TTP 血清的上调。我们将检查 人微血管 EC 与 TTP 相互作用的免疫生物学 来自 HIV+ 和 HIV 血清阴性个体的血清和血浆、TNF-α、 从 TTP 患者和 HIV 感染的单核细胞中分离出抗 CD36。 将在大型容器 EC 的平行实验中寻求特异性， 不受TTP病理过程的影响。 该提案试图统一并相互关联几个不同的 TTP 的观察特征：血小板血栓形成 仅限于微血管，伴有 EC 增殖， 损伤和内皮下层暴露，所有这些都是在没有 炎症反应。基于 Fas/Fas 的可能性 TTP 等离子体促进配体相互作用和 CD36 交联 导致微血管EC激活的因素、蛋白激酶 诱导、EC 凋亡以及血小板聚集，我们将 研究开发基于 TTP 的特异性治疗方法的可能性 蛋白激酶抑制剂和 CD36 肽。 （摘要完）