The Molecular and Genetic Pathogensis of LAM

 描述（由申请方提供）：淋巴管平滑肌瘤病（LAM）是一种女性破坏性多系统疾病，特征为囊性肺破坏、肾血管平滑肌脂肪瘤和乳糜性胸腔积液。淋巴管生成在肺LAM结节中突出，血清VEGF-D是LAM的诊断生物标志物。大多数LAM细胞在结节性硬化症（TSC）基因中携带双等位基因失活突变，并且可以在血液中检测到具有TSC 2杂合性缺失的循环LAM细胞。 TSC蛋白复合物通过小GTdR heb抑制雷帕霉素的哺乳动物/机制靶标（mTORC 1）（图1）。mTORC 1作为一种分子传感器，调节细胞生长、代谢、自噬和microRNA生物合成。在LAM和TSC中，临床试验已经证明了西罗莫司（雷帕霉素）或其类似物（雷帕霉素类似物）治疗的临床益处。总的来说，这些数据表明雷帕霉素是一种有效的LAM抑制疗法。然而，当停药时，肺功能恢复下降，肿瘤重新生长。因此，治疗必须长期使用-也许是终身使用。这突出了对LAM和TSC中的新型治疗策略和/或允许以最低有效水平给予雷帕霉素以使益处最大化并使风险最小化的机制的迫切未满足的需求。 该UO 1汇集了LAM研究的独特领导团队，以解决具有高度临床影响的关键未回答的问题。首先，导致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”测序定量并用作LAM的生物标志物？第三，对散发性LAM的遗传基础进行更精细的解剖是否能揭示广泛的低水平TSC 2嵌合体？第四，包括VEGF-D和microRNA在内的生物标志物能否用于制定西罗莫司给药的个性化策略？ 叙述：该UO 1汇集了淋巴管平滑肌瘤病（LAM）和结节性硬化症（TSC）的独特领导团队，以解决具有高度临床影响的关键未回答问题。首先，导致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”测序定量并用作LAM的生物标志物？第三，对散发性LAM的遗传基础进行更精细的解剖是否能揭示广泛的低水平TSC 2嵌合体？第四，包括VEGF-D和microRNA在内的生物标志物能否用于制定西罗莫司给药的个性化策略？

 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?