The Molecular and Genetic Pathogensis of LAM

 描述(申请人提供)：淋巴管肌瘤病(LAM)是一种女性的破坏性多系统疾病，以囊性肺破坏、肾血管肌脂肪瘤和乳糜性胸腔积液为特征。淋巴管生成在肺LAM结节中显著，血清VEGF-D是LAM的诊断生物标志物。大多数LAM细胞携带结节性硬化症复合体(TSC)基因的双等位基因失活突变，在血液中可以检测到具有TSC2杂合性缺失的循环LAM细胞。 TSC蛋白复合体通过小GTP酶Rheb抑制雷帕霉素的哺乳动物/机械靶点(MTORC1)(图1)。MTORC1作为一个分子传感器，调节细胞生长、代谢、自噬和microRNA的生物发生。关键的临床试验已经证明，在LAM和TSC中使用西罗莫司(雷帕霉素)或其类似物(拉帕洛格)治疗有临床益处。总体而言，这些数据表明雷帕霉素是一种有效的LAM抑制疗法。然而，当药物停止使用时，肺功能会恢复下降，肿瘤会重新生长。因此，治疗必须是长期的--也许是终生的。这突显了LAM和TSC对新的治疗策略和/或机制的迫切需求，这些策略和/或机制允许以最低有效水平给药雷帕霉素，以最大限度地提高效益和最大限度地降低风险。 UO1汇集了LAM研究领域独特的领导者团队，以解决具有高度临床影响的关键悬而未决的问题。首先，LAM淋巴管生成的基本机制是什么？第二，循环LAM细胞负荷能否通过“下一代”测序来量化，并作为LAM的生物标志物？第三，对散发性LAM的遗传基础进行更细致的剖析是否会揭示普遍的低水平TSC2嵌合体？第四，包括血管内皮生长因子-D和微RNA在内的生物标记物能否用于制定西罗莫司的个性化给药策略？ 简介：UO1汇集了淋巴管肌瘤病(LAM)和结节性硬化症(TSC)领域独特的领导者团队，以解决具有高度临床影响的关键未解答问题。首先，LAM淋巴管生成的基本机制是什么？第二，循环LAM细胞负荷能否通过“下一代”测序来量化，并作为LAM的生物标志物？第三，对散发性LAM的遗传基础进行更细致的剖析是否会揭示普遍的低水平TSC2嵌合体？第四，包括血管内皮生长因子-D和微RNA在内的生物标记物能否用于制定西罗莫司的个性化给药策略？

 DESCRIPTION (provided by applicant): Lymphangioleiomyomatosis (LAM) is a destructive multi-system disease of women characterized by cystic lung destruction, renal angiomyolipomas, and chylous pleural effusions. Lymphangiogenesis is prominent in pulmonary LAM nodules and serum VEGF-D is diagnostic biomarker of LAM. The majority of LAM cells carry bi-allelic inactivating mutations in the tuberous sclerosis complex (TSC) genes and circulating LAM cells with TSC2 loss of heterozygosity can be detected in the blood. The TSC protein complex inhibits the mammalian/mechanistic target of rapamycin (mTORC1) via the small GTPase Rheb (Fig.1). mTORC1 acts as a molecular sensor that regulates cell growth, metabolism, autophagy, and microRNA biogenesis. Pivotal clinical trials have demonstrated clinical benefit from treatment with sirolimus (Rapamycin) or its analogs (Rapalogs) in LAM and TSC. Collectively these data indicate that Rapamycin is an effective suppressive therapy for LAM. However, lung function decline resumes and tumors regrow when the drug is discontinued. Therefore, therapy must be used chronically - perhaps lifelong. This highlights the urgent unmet need for novel therapeutic strategies in LAM and TSC and/or mechanisms to allow Rapamycin to be dosed at the lowest effective level, to maximize benefit and minimize risk. This UO1 brings together a unique team of leaders in LAM research to address key unanswered questions with high clinical impact. First, what are the fundamental mechanisms leading to lymphangiogenesis in LAM? Second, can circulating LAM cell burden be quantitated through "next generation" sequencing and used as a biomarker of LAM? Third, will finer dissection of the genetic basis of sporadic LAM reveal generalized low-level TSC2 mosaicism? Fourth, can biomarkers including VEGF-D and microRNA be used to develop personalized strategies for sirolimus dosing? Narrative: This UO1 brings together a unique team of leaders in lymphangioleiomyomatosis (LAM) and tuberous sclerosis complex (TSC) to address key unanswered questions with high clinical impact. First, what are the fundamental mechanisms leading to lymphangiogenesis in LAM? Second, can circulating LAM cell burden be quantitated through "next generation" sequencing and used as a biomarker of LAM? Third, will finer dissection of the genetic basis of sporadic LAM reveal generalized low-level TSC2 mosaicism? Fourth, can biomarkers including VEGF-D and microRNA be used to develop personalized strategies for Sirolimus dosing?