The Molecular and Genetic Pathogensis of LAM

LAM 的分子和遗传发病机制

• 批准号: 9038505
• 负责人: Elizabeth P Henske
• 金额: $ 75.49万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-21 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9038505
• 关键词: Address; Autophagocytosis; Biogenesis; Biological Markers; Blood; Blood Cells; CCL2 gene; Cell Count; Cells; Clinical; Clinical Trials; Collaborations; Collecting Cell; Cyst; Data; Development; Disease; Dissection; Doctor of Philosophy; Dose; Extramural Activities; FRAP1 gene; Future; Gene Frequency; Genes; Genetic; Intramural Research Program; Link; Loss of Heterozygosity; Lung; Lymphangiogenesis; Lymphangioleiomyomatosis; Metabolism; MicroRNAs; Molecular; Molecular Genetics; Monomeric GTP-Binding Proteins; Mosaicism; Mosses; Mutation; Nodule; Patients; Pharmaceutical Preparations; Pleural effusion disorder; Primary Cell Cultures; Pulmonary function tests; Renal Angiomyolipoma; Research; Resources; Respiratory physiology; Risk; Serum; Severity of illness; Sirolimus; Source; Surrogate Markers; System; TSC1/2 gene; TSC2 gene; Tissues; Toxic effect; Tuberous sclerosis protein complex; United States National Institutes of Health; Up-Regulation; Vascular Endothelial Growth Factor D; Woman; Work; analog; base; candidate marker; cell growth; cell type; circulating microRNA; combinatorial; design; diagnostic biomarker; mutant; next generation sequencing; novel marker; novel therapeutics; overexpression; personalized strategies; programs; protein complex; response; sensor; treatment response; tumor

 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?

 描述（由申请人提供）：淋巴管平滑肌瘤病 (LAM) 是一种女性破坏性多系统疾病，其特征为囊性肺破坏、肾血管平滑肌脂肪瘤和乳糜性胸腔积液，肺 LAM 结节中淋巴管生成很明显，血清 VEGF-D 是该疾病的诊断生物标志物。 LAM。大多数 LAM 细胞携带结节性硬化症 (TSC) 基因的双等位基因失活突变。血液中可检测到 TSC2 杂合性缺失的循环 LAM 细胞。 TSC 蛋白复合物通过小 GTP 酶 Rheb 抑制哺乳动物/雷帕霉素的机械靶点（mTORC1）（图 1），mTORC1 充当调节细胞生长、代谢、自噬和 microRNA 生物发生的分子传感器。在 LAM 和 TSC 中使用西罗莫司（雷帕霉素）或其类似物（Rapalogs）治疗的临床益处总的来说，这些数据表明雷帕霉素是一种治疗药物。然而，当停药时，肺功能会恢复，肿瘤会重新生长，因此，治疗必须长期使用——也许是终生，这凸显了对 LAM 和 TSC 和/或机制的新治疗策略的迫切需求。允许雷帕霉素以最低有效水平给药，以最大限度地提高效益并最大限度地降低风险。 UO1 汇集了 LAM 研究领域的独特领导者团队，旨在解决具有高度临床影响的关键未解答问题：首先，导致 LAM 淋巴管生成的基本机制是什么？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剖析是否会揭示普遍的低水平 TSC2 嵌合体？第四，包括 VEGF-D 和microRNA 可用于制定西罗莫司给药的个性化策略？ 叙述：UO1 汇集了淋巴管平滑肌瘤病 (LAM) 和结节性硬化症 (TSC) 领域的独特领导团队，以解决具有重大临床影响的关键未解答问题：第一，导致 LAM 淋巴管生成的基本机制是什么？ LAM 细胞负荷可以通过“下一代”测序进行定量并用作 LAM 的生物标志物吗？第三，对散发性 LAM 的遗传基础进行更精细的剖析是否会揭示普遍性？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？