RAPAMYCIN THERAPY OF RENAL ANGIOMYOLIPOMAS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。大约每5，000人中就有一人患有结节性硬化症（TSC），代表美国约56，000名患者和全球100万名患者。这种疾病的过程不集中在种族群体中，也没有性别偏好。肾功能衰竭已被报道是导致成人结节性硬化症患者死亡的主要原因，在大多数情况下，由于健康的肾脏组织被称为血管平滑肌脂肪瘤的脂肪肿瘤替代。 大约40%的TSC女性患者还发展为称为淋巴管平滑肌瘤病（LAM）的肺部疾病。LAM的特征在于肺中的平滑肌细胞浸润，导致肺组织囊性变性、气体交换受损、呼吸衰竭和死亡。最近有证据表明，LAM可能是由血管平滑肌脂肪瘤细胞转移到肺部引起的。 血管平滑肌脂肪瘤细胞特别容易受到从TSC基因中选择正确基因产物的治疗。TSC 1的基因产物hamartin和TSC 2的基因产物tuberin是调节细胞生长的途径中的关键参与者。雷帕霉素模拟在TSC中功能失调的块茎蛋白/错构瘤蛋白复合物的功能。雷帕霉素抑制来自人、大鼠、小鼠和苍蝇的块茎蛋白和错构蛋白缺陷细胞的生长，并在大鼠和小鼠中产生肿瘤消退。因此，本研究的目的是确定雷帕霉素给药是否可以减少或消除TSC和散发性LAM患者的血管平滑肌脂肪瘤，就像在人细胞培养和动物模型中一样。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Approximately one out of 5,000 individuals has tuberous sclerosis complex (TSC), representing approximately 56,000 patients in the United States and 1 million patients worldwide. This disease process does not cluster in ethnic groups and has no gender predilection. Renal failure has been reported to be the leading cause of death in adult tuberous sclerosis patients, in most cases due to replacement of healthy kidney tissue by fatty tumors called angiomyolipomas. Approximately 40% of female patients with TSC also develop a pulmonary disease called lymphangioleiomyomatosis (LAM). LAM is characterized by smooth muscle cell infiltration in the lungs leading to cystic degeneration of lung tissue, impaired gas exchange, respiratory failure and death. There is recent evidence that LAM may be caused by metastases of angiomyolipoma cells to the lung. Angiomyolipoma cells are uniquely vulnerable to treatments that select for the presence of the correct gene product from the TSC genes. The gene products of TSC1, hamartin, and TSC2, tuberin, are key players in a pathway that regulates cell growth. Rapamycin mimics the function of the tuberin/hamartin complex, which is dysfunctional in TSC. Rapamycin inhibits the growth of tuberin and hamartin deficient cells from humans, rats, mice and flies, and produces tumor regression in rats and mice. Thus, the aim of this study is to determine if the administration of Rapamycin can reduce or eliminate angiomyolipomas in patients with TSC and sporadic LAM as it does in human cell culture and animal models.