The Molecular and Genetic Pathogenesis of LAM

LAM 的分子和遗传发病机制

基本信息

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
项目类别：
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

项目摘要

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.

抽象的淋巴管平滑肌瘤病 (LAM) 是一种女性进行性多系统疾病，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是显着的。肺 LAM 结节中的 VEGF-D 水平和血清 VEGF-D 水平高于 800 pg/ml 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，可以在血液中检测到 TSC2 杂合性缺失的循环 LAM 细胞。 TSC 蛋白复合物通过小 GTP 酶 Rheb。mTORC1 作为分子传感器，调节细胞生长、代谢、自噬、关键临床试验已证明西罗莫司治疗具有临床益处。 LAM 和 TSC 中的（雷帕霉素）或其类似物（Rapalogs）这些数据共同表明雷帕霉素是一种。对 LAM 进行有效的抑制治疗，但肺功能会恢复，肿瘤会重新生长。因此，必须长期使用治疗——也许是终身治疗。 LAM 和 TSC 中对消除（而不是抑制）LAM 细胞的新治疗策略的需求尚未得到满足新型生物标志物允许个性化治疗并更好地了解遗传和临床因素可能有助于预测 LAM 的严重程度。 UO1 汇集了淋巴管平滑肌瘤病 (LAM) 和结节性肌瘤领域独特的领导团队硬化症综合体（TSC）来解决具有高度临床影响的关键未解答问题首先，确定新的。使用 LAM 的体外和体内模型以及人类 LAM 的单细胞 RNA 测序。肺部，对 LAM 细胞“分泌组”的系统分析将阐明 LAM 的发病机制，揭示新的机制其次，研究导致 LAM 细胞的新型 mTORC1 独立途径。第三，分析 LAM 细胞的遗传修饰因子。 LAM 和 TSC2 基因突变的潜在隐秘广义体细胞嵌合现象以阐明 LAM 发病机制并帮助识别进展风险最高的患者。