PATHOGENESIS OF HIV ASSOCIATED HUS/TTP IN CHILDREN

血栓性血小板减少性紫癜性溶血性尿毒症综合征(TTP-HUS) 特点是微血管病理性溶血性贫血，血小板减少， 中枢神经系统异常和肾功能障碍。本综合征 成人以神经系统症状为主，儿童以肾功能衰竭为主。 微血管血栓形成是典型的病变，内皮细胞损伤是 很可能是最初的事件。基于其他调查人员之前的研究 以及我们从感染艾滋病毒的儿童身上获得的临床和病理数据- 与HUS/TTP相关，我们假设预后越严重 HIV-1感染儿童的HUS/TTP部分与HIV-1增强有关 微血管损伤和细胞行为与再灌注相关 肾毛细血管内皮化。我们获得的初步数据 从HIV-1转基因小鼠和携带HIV相关HUS/TTP的儿童， 表明HIV-1刺激细胞外基质蛋白的合成， 肾微血管的黏附、生长和组织分化。 这些变化促进了血栓性毛细血管阻塞， 延缓再通过程，导致慢性肾功能衰竭 因全身微血管受累而失败或死亡。三个具体的 提出了目标。首先，我们将确定培养的人类肾脏是否 微血管内皮细胞暴露在空气中时会受到感染和损伤 来源的无细胞病毒粒子或HIV-1感染的淋巴细胞/巨噬细胞 患有HIV相关HUS-TTP的儿童。第二，我们将评估增长， 肾脏的黏附、迁移与形态分化 体外微血管内皮细胞，在有或没有TAT的情况下 或者是HIV-1病毒。TAT-HIV-1调节这些细胞因子的机制 行为将通过描述已经被 与血管管腔的再通道化有关，包括基质 整合素的蛋白质合成、迁移、分化和表达 受体，以及细胞外基质蛋白酶的产生。第三，基于 根据这些结果，我们将开发出一种艾滋病毒的转基因小鼠模型 关联的HUS/TTP。我们预计这些实验将决定人们的反应 肾微血管内皮细胞对HIV-1病毒的研究，提供了有用的 关于HIV-1对肾内皮细胞行为调节的数据 在再通管的过程中，并建立一个临床相关的 用动物模型测试抗HIV相关HUS/TTP的新疗法 孩子们。

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.