RAPAMYCIN THERAPY OF RENAL ANGIOMYOLIPOMAS

雷帕霉素治疗肾血管平滑肌脂肪瘤

• 批准号: 7607742
• 负责人: JOHN J BISSLER
• 金额: $ 1万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-15 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7607742
• 关键词: Adult; Angiomyolipoma; Animal Model; Cause of Death; Cells; Cessation of life; Complex; Computer Retrieval of Information on Scientific Projects Database; Cultured Cells; Disease; Disease regression; Ethnic group; Female; Funding; Gases; Gender; Genes; Grant; Growth; Human; Individual; Infiltration; Institution; Kidney; Kidney Failure; Lipoma; Lung; Lung diseases; Lymphangioleiomyomatosis; Mus; Neoplasm Metastasis; Pathway interactions; Patients; Process; Proteins; Rattus; Renal Angiomyolipoma; Reporting; Research; Research Personnel; Resources; Respiratory Failure; Sirolimus; Smooth Muscle Myocytes; Source; Structure of parenchyma of lung; TSC1 gene; Tissues; Tuberous Sclerosis; Tuberous sclerosis protein complex; United States; United States National Institutes of Health; cell growth; fly; human TSC1 protein; human TSC2 protein; tumor

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.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 大约每 5,000 人中就有 1 人患有结节性硬化症 (TSC)，美国约有 56,000 名患者，全球约有 100 万患者。 这种疾病过程不分种族，也没有性别偏好。 据报道，肾衰竭是成人结节性硬化症患者死亡的主要原因，在大多数情况下，由于健康的肾组织被称为血管平滑肌脂肪瘤的脂肪肿瘤取代。 大约 40% 的 TSC 女性患者还会患上一种称为淋巴管平滑肌瘤病 (LAM) 的肺部疾病。 LAM 的特点是肺部平滑肌细胞浸润，导致肺组织囊性变、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至肺部引起的。 血管平滑肌脂肪瘤细胞特别容易受到选择 TSC 基因中正确基因产物存在的治疗的影响。 TSC1（错构蛋白）和 TSC2（马铃薯蛋白）的基因产物是调节细胞生长途径的关键角色。 雷帕霉素模仿马铃薯蛋白/错构蛋白复合物的功能，该复合物在 TSC 中功能失调。 雷帕霉素抑制人、大鼠、小鼠和果蝇的马铃薯球蛋白和错构蛋白缺陷细胞的生长，并使大鼠和小鼠的肿瘤消退。 因此，本研究的目的是确定给予雷帕霉素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，就像在人类细胞培养物和动物模型中那样。