The Molecular and Genetic Pathogenesis of LAM

LAM 的分子和遗传发病机制

• 批准号: 10563145
• 负责人: Elizabeth P Henske
• 金额: $ 68.56万
• 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 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10563145
• 关键词: Address; Alleles; Alveolar Cell; Angiomyolipoma; Autophagocytosis; Award; Biogenesis; Biological Markers; Blood; Cell Death; Cell Survival; Cells; Chronic; Clinical; Clinical Research; Clinical Trials; Collaborations; Cyst; Data; Data Set; Development; Diagnostic; Disease; Disease Progression; Disease model; Doctor of Philosophy; Early identification; Extramural Activities; FRAP1 gene; Fibroblasts; Gene Mutation; Genes; Genetic; Goals; Human; Immunocompetent; In Vitro; Interleukin-6; Intramural Research Program; Longitudinal Studies; Loss of Heterozygosity; Lung; Lung Lymphangioleiomyomatosis; Lymphangiogenesis; Lymphangioleiomyomatosis; Manuscripts; Metabolism; MicroRNAs; Modeling; Molecular; Monomeric GTP-Binding Proteins; Mosaicism; Mosses; Mus; Mutation; New Agents; Nodule; Pathogenesis; Pathway interactions; Patients; Pattern; Peer Review; Pharmaceutical Preparations; Phase; Phenotype; Plasma; Pleural effusion disorder; Preparation; Prevalence Study; Prognostic Marker; Protein Secretion; Protocols documentation; Publishing; Renal Angiomyolipoma; Research; Resources; Risk; Safety; Serum; Severities; Sirolimus; System; TSC2 gene; Testing; Therapeutic; Therapeutic Uses; Toxic effect; Tuberous Sclerosis; Tuberous sclerosis protein complex; United States National Institutes of Health; Vascular Endothelial Growth Factor D; Woman; Work; alveolar destruction; analog; apoAI regulatory protein-1; celecoxib; cell growth; clinical center; clinical phenotype; clinically relevant; diagnostic biomarker; disorder risk; dosage; early detection biomarkers; genetic analysis; genome sequencing; genome wide association study; high risk; human RNA sequencing; in vivo Model; member; mouse model; novel; novel marker; novel therapeutic intervention; participant enrollment; personalized care; personalized medicine; programs; progression risk; protein complex; pulmonary function; pulmonary function decline; recruit; research study; response; sensor; single-cell RNA sequencing; therapeutic target; tumor; tumor-immune system interactions; whole genome

Abstract Lymphangioleiomyomatosis (LAM) is a progressive 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 levels above 800 pg/ml are a 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. 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 to eliminate (rather than suppress) LAM cells, for novel biomarkers allowing personalization of therapy and to better understand genetic and clinical factors that may help to predict the severity of LAM. 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, identifying novel biomarkers of LAM. Using in vitro and in vivo models of LAM and single cell RNA sequencing from human LAM lungs, systematic analysis of the LAM cell “secretome” will elucidate the pathogenesis of LAM revealing novel prognostic biomarkers. Second, investigating novel mTORC1-independent pathways leading to LAM cell survival that could be therapeutically targeted to induce LAM cell death. Third, analysis of genetic modifiers of LAM and of potential cryptic generalized somatic mosaicism for TSC2 gene mutations to elucidate LAM pathogenesis and help identify patients at highest risk of progression.

抽象的 淋巴血管瘤瘤病（L​​AM）是一种促进性的多系统疾病，其特征是 囊性肺破坏，肾血管肌层瘤和猫胸腔积液。淋巴管生成很突出 在800 pg/ml的肺LAM结节和血清VEGF-D水平中，是LAM的诊断生物标志物。这 大多数LAM细胞在结节性硬化症复合物（TSC）基因中携带双重持续失活突变和 可以在血液中检测到具有TSC2杂合性丧失的循环LAM细胞。 TSC蛋白复合物抑制雷帕霉素（MTORC1）的哺乳动物/机械靶标 小GTPase Rheb。 MTORC1充当调节细胞生长，代谢，自噬， 和microRNA生物发生。关键临床试验表明，西罗莫司治疗的临床益处 （雷帕霉素）或LAM和TSC中的类似物（Rapalogs）。这些数据指示雷帕霉素是 有效的LAM抑制疗法。但是，肺功能下降恢复，肿瘤改革当 药物停产。因此，必须长期使用治疗 - 也许是终身。这突出了紧急 未满足的LAM和TSC中新型治疗策略的需求，以消除（而不是抑制）LAM细胞，用于 新型生物标志物允许对治疗的个性化并更好地了解遗传和临床因素 可能有助于预测LAM的严重性。 该UO1汇集了一个独特的淋巴管肌瘤（LAM）和结节的独特领导者团队 硬化症复合物（TSC），以临床影响很高，以解决关键的未解决问题。首先，识别小说 林的生物标志物。使用人LAM的LAM和单细胞RNA测序的体外和体内模型 肺，对LAM细胞“分泌组”的系统分析将阐明LAM的发病机理揭示了新型 预后生物标志物。其次，研究了导致LAM细胞的新型MTORC1独立途径 可以热靶向诱导LAM细胞死亡的生存。第三，分析的遗传修饰符 LAM和潜在的加密通用体镶嵌物用于TSC2基因突变以阐明LAM 发病机理并帮助识别出最高进展风险的患者。