PATHOGENESIS OF HIV ASSOCIATED HUS/TTP IN CHILDREN

儿童 HIV 相关 HUS/TTP 的发病机制

• 批准号: 2234207
• 负责人: PATRICIO E RAY
• 金额: $ 28.6万
• 依托单位: CHILDREN'S NATIONAL MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-07-01 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2234207
• 关键词: PATHOGENESIS; HIV; ASSOCIATED; HUS; TTP

Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) is characterized by microangiopathic hemolytic anemia, thrombocytopenia, central nervous system abnormalities, and renal dysfunction. This syndrome is dominated by neurological signs in adults and renal failure in children. Microvascular thrombosis is the typical lesion and endothelial injury is likely the initial event. Based on previous studies by other investigators and our own clinical and pathological data obtained from children with HIV- associated HUS/TTP, we hypothesized that the more severe prognosis of HUS/TTP in HIV-1 infected children is related tin part to HIV-1 enhancement of microvascular injury and cell behaviors associated with re- endothelialization of renal capillaries. Our preliminary data obtained from HIV-1 transgenic mice and children with HIV associated HUS/TTP, indicate that HIV-1 stimulates synthesis of extracellular matrix proteins, adhesion, growth and organization/differentiation of renal microvessels. These changes facilitate the thrombotic obstruction of capillaries, delaying the process of re-canalization and leading to chronic renal failure or death due to systemic microvascular involvement. Three specific aims are proposed. First, we will determine whether cultured human renal microvascular endothelial cells are infected and injured when exposed to cell free virions or to HIV-1 infected lymphocytes/macrophages derived from children with HIV associated HUS-TTP. Second, we will evaluate growth, adhesion, migration and morphological differentiation of renal microvascular endothelial cells in vitro, in the presence or absence of tat or the HIV-1 virus. The mechanisms by which tat -HIV-1 modulate these behaviors will be examined by characterizing activities that have been associated with re-canalization of the vascular lumen including, matrix protein synthesis, migration, differentiation, expression of integrin receptors, and production of extracellular matrix proteases. Third, based on these results, we will develop a transgenic mouse model of HIV associated HUS/TTP. We expect these experiments will define the response of the renal microvascular endothelium to the HIV-1 virus, provide useful data regarding the modulation of renal endothelial cell behaviors by HIV-1 during the process of re-canalization, and establish a clinically relevant animal model to test novel therapies against HIV-associated HUS/TTP in children.

血栓性血小板减少性紫癜-溶血性尿毒综合征（TTP-HUS）是一种 其特征在于微血管病性溶血性贫血，血小板减少症， 中枢神经系统异常和肾功能障碍。 这种综合征 主要表现为成人的神经系统症状和儿童的肾衰竭。 微血管血栓形成是典型的病变， 可能是最初的事件。 根据其他研究人员先前的研究， 以及我们自己从艾滋病儿童身上获得的临床和病理数据- 与HUS/TTP相关，我们假设HUS/TTP越严重， HIV-1感染儿童的HUS/TTP与HIV-1增强部分相关 微血管损伤和细胞行为与再- 肾毛细血管内皮化。 我们获得的初步数据 从HIV-1转基因小鼠和患有HIV相关HUS/TTP的儿童， 表明HIV-1刺激细胞外基质蛋白的合成， 肾脏微血管的粘附、生长和组织/分化。 这些变化促进毛细血管的血栓性阻塞， 延迟再通过程并导致慢性肾功能衰竭 由于全身微血管受累而导致的衰竭或死亡。 三个具体 提出了目标。 首先，我们将确定培养的人类肾脏 微血管内皮细胞在暴露于 无细胞病毒体或HIV-1感染的淋巴细胞/巨噬细胞， HIV相关HUS-TTP儿童。 其次，我们将评估增长， 粘附、迁移和肾组织形态分化 在存在或不存在达特的情况下，体外微血管内皮细胞 或者HIV-1病毒。 达特-1调节这些的机制 行为将通过描述已经被 与血管腔的再通相关，包括基质 蛋白质合成、迁移、分化、整合素表达 受体和细胞外基质蛋白酶的产生。 三是立足 基于这些结果，我们将开发一种HIV转基因小鼠模型 相关HUS/TTP。 我们希望这些实验能够定义 肾微血管内皮细胞的HIV-1病毒，提供有用的 HIV-1对肾内皮细胞行为的调节数据 在再通过程中，并建立临床相关的 动物模型来测试针对HIV相关HUS/TTP的新疗法， 孩子