PATHOGENESIS OF HIV ASSOCIATED HUS/TTP IN CHILDREN

儿童 HIV 相关 HUS/TTP 的发病机制

• 批准号: 6030721
• 负责人: PATRICIO E RAY
• 金额: $ 41.08万
• 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 2001-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6030721
• 关键词: HIV infections; cell adhesion; cell cycle; cell differentiation; cell migration; child (0-11); disease /disorder model; enzyme linked immunosorbent assay; extracellular matrix proteins; genetically modified animals; hemolytic anemia; integrins; kidney circulation; laboratory mouse; microcirculation; murine AIDSs; pathologic process; polymerase chain reaction; prognosis; thrombocytopenic purpura; thrombosis; tissue /cell culture; uremias; vascular endothelium; virion; virus infection mechanism

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-溶血性尿毒症综合征（TTP-HUS）是 以微血管病性溶血性贫血、血小板减少症为特征， 中枢神经系统异常、肾功能障碍。 这种综合症 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病变，内皮损伤是 可能是最初的事件。 基于其他研究人员之前的研究 以及我们自己从艾滋病毒儿童身上获得的临床和病理数据- 相关的 HUS/TTP，我们假设预后越严重 HIV-1 感染儿童中的 HUS/TTP 与 HIV-1 增强有关 与再相关的微血管损伤和细胞行为 肾毛细血管内皮化。 我们得到的初步数据 来自 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， 肾微血管的粘附、生长和组织/分化。 这些变化促进了毛细血管的血栓性阻塞， 延迟再通过程并导致慢性肾病 由于全身微血管受累而导致衰竭或死亡。 三具体 提出了目标。 首先，我们要确定是否培养了人肾 当接触到微血管内皮细胞时，微血管内皮细胞会被感染和损伤。 无细胞病毒颗粒或来自 HIV-1 感染的淋巴细胞/巨噬细胞 患有 HIV 相关 HUS-TTP 的儿童。 其次，我们将评估增长， 肾组织的粘附、迁移和形态分化 体外微血管内皮细胞，存在或不存在tat 或 HIV-1 病毒。 tat-HIV-1调节这些的机制 行为将通过表征活动进行检查 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、立足 根据这些结果，我们将开发艾滋病毒转基因小鼠模型 相关的 HUS/TTP。 我们预计这些实验将定义响应 肾微血管内皮细胞对 HIV-1 病毒的影响，提供有用的 有关 HIV-1 调节肾内皮细胞行为的数据 在再通过程中，建立临床相关的 用于测试针对 HIV 相关 HUS/TTP 的新疗法的动物模型 孩子们。