APOPTOSIS OF MICROVASCULAR ENDOTHELIAL CELLS IN HUS

HUS 中微血管内皮细胞的凋亡

• 批准号: 2887443
• 负责人: JEFFREY C LAURENCE
• 金额: $ 29.59万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-23 至 2001-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2887443
• 关键词: apoptosis; capillary; clinical research; enzyme induction /repression; hemolytic anemia; human subject; interleukin 1; postmortem; protein kinase; renal failure; thrombocytopenic purpura; tissue /cell culture; tumor necrosis factor alpha; vascular endothelium

DESCRIPTION: The hypothesis for this project is that plasma factors, including Fas ligand (FasL)-related molecules, IL-l, and tumor necrosis factor (TNF)-alpha, play an etiologic role in HUS through induction of microvascular endothelial cell (EC) apoptosis. This is based upon three observations that we have made: plasma from patients with acute HUS induces apoptosis in microvascular EC of the kidney and certain other lineages, but not in large vessel or pulmonary microvascular EC; IL-l or TNF-alpha or both are up-regulated in subsets of HUS, reaching concentrations associated with apoptosis of EC in vitro; and acute HUS plasma induces the apoptosis-linked molecule Fas on subsets of microvascular EC, paralleling nuclear translocation of protein phosphokinases implicated in final common pathways to apoptosis. This hypothesis is consistent with the pathology of HUS, as EC activation, and detachment occur in the absence of an inflammatory response (one hallmark of apoptosis). We will examine the immunobiology of renal and other primary human microvascular EC in terms of interactions with HUS plasma, fractions of normal plasma, Fas, and a new member of the FasL family, which we have found on subsets of microvascular EC negative for FasL. Specificity will be sought using large vessel EC and pulmonary microvascular EC, which are not affected in HUS, and compared with the effect of plasmas from subsets of patients with a related thrombopathy, thrombotic thrombocytopenic purpura (TTP), who show limited renal pathology. In vivo evidence for apoptosis will be sought using HUS autopsy and biopsy material. Based upon the premise that Fas/FasL-like interactions are facilitated by HUS plasma factors, leading to microvascular EC activation, protein kinase induction, and EC apoptosis, we will examine the possibility of developing treatments involving inhibitors of apoptosis.

描述：该项目的假设是血浆因素， 包括Fas配体（FasL）相关分子、IL-1和肿瘤坏死 因子 (TNF)-α，通过诱导 HUS 发挥病因作用 微血管内皮细胞（EC）凋亡。 这是基于三 我们所做的观察：来自急性 HUS 患者的血浆 诱导肾脏微血管 EC 和某些其他细胞凋亡 谱系，但不在大血管或肺微血管 EC 中； IL-1或 TNF-α 或两者在 HUS 亚群中上调，达到 与体外 EC 凋亡相关的浓度；和急性 HUS 血浆诱导细胞凋亡相关分子 Fas 的子集 微血管 EC，平行蛋白质核转位 涉及细胞凋亡最终共同途径的磷酸激酶。 这 假设与 HUS 的病理学一致，因为 EC 激活， 并且脱离发生在没有炎症反应的情况下（一种 细胞凋亡的标志）。 我们将检查肾脏和肾脏的免疫生物学 其他原发性人类微血管 EC 与 HUS 的相互作用 血浆、正常血浆成分、Fas 和 FasL 的新成员 家族，我们在微血管 EC 的子集中发现了阴性 FasL。 将使用大血管 EC 和肺来寻求特异性 微血管 EC 在 HUS 中不受影响，并且与 来自患有相关血栓病的患者亚群的血浆的影响， 血栓性血小板减少性紫癜（TTP），表现为肾功能受限 病理。 将使用 HUS 寻找细胞凋亡的体内证据 尸检和活检材料。 基于Fas/FasL-like的前提 HUS 血浆因子促进相互作用，导致 微血管 EC 激活、蛋白激酶诱导和 EC 凋亡， 我们将研究开发治疗方法的可能性，涉及 细胞凋亡抑制剂。