Molecular Biomarkers in pathogenesis of Lymphangioleiomyomatosis (LAM)

淋巴管平滑肌瘤病 (LAM) 发病机制中的分子生物标志物

• 批准号: 10745193
• 负责人: Jeanine M D'Armiento
• 金额: $ 66.86万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-10 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10745193
• 关键词: Age; Architecture; BMP5 gene; Behavior; Biological Markers; Blood; CRISPR/Cas technology; Candidate Disease Gene; Cell Differentiation process; Cell Line; Cell Proliferation; Cell physiology; Cells; Cessation of life; Clinical; Computational Technique; Diagnosis; Disease; Disease Progression; Drug Targeting; FRAP1 gene; Gender; Gene Expression; Genes; Genetic; Growth; HMGA2 gene; Histologic; Human; IGFBP2 gene; IGFBP4 gene; IGFBP5 gene; In Vitro; Individual; Knock-out; Laboratories; Lung; Lung Lymphangioleiomyomatosis; Lung diseases; Lymphangioleiomyomatosis; Measures; Medical; Mesenchymal; Messenger RNA; Modeling; Mus; Mutation; Oncogenic; Participant; Pathogenesis; Pathway interactions; Patients; Prognosis; Proliferating; Publishing; Respiratory Failure; Role; Sampling; Serum; Severities; Signal Pathway; Smooth Muscle Myocytes; Subcutaneous Injections; TSC2 gene; Tail; Techniques; Testing; Therapeutic Intervention; Tuberous Sclerosis; Tumor Cell Line; Veins; Whole Blood; cell behavior; cell growth; cell type; cohort; disease phenotype; genome editing; indexing; induced pluripotent stem cell; lung lesion; mRNA Expression; molecular marker; mouse model; neoplastic cell; new therapeutic target; novel; patient subsets; pharmacologic; response; transcription factor; transcriptome sequencing; tumor; tumor initiation; tumor microenvironment; tumorigenesis; validation studies

Project Summary Lymphangioleiomyomatosis (LAM) is a progressive lung disease which can lead to respiratory failure and potential death. LAM is treated with drugs targeting the mammalian target of rapamycin (mTOR) pathway however, only a subset of patients responds to the treatment which is transient and not curative. Interestingly, there are numerous studies which have suggested that other pathways are important in the pathogenesis of the disease. Our laboratory has demonstrated that high mobility group HMGA2, a non-histone chromosomal architectural transcription factor, is critical in the pathogenesis of LAM. Published studies from our group demonstrate that HMGA2 is required for the mesenchymal tumorigenesis in the tuberous sclerosis (Tsc2+/-) mouse model. We therefore hypothesize that the HMGA2 signaling pathway drives the pathogenesis of tumors initiated in the TSC2 haploinsufficiency state in LAM. Furthermore, we postulate that the expression of HMGA2 and its oncogenic pathway genes can be used clinically for LAM diagnosis and potential prognosis. To test our hypotheses, we propose the following objectives: In the first aim our studies we will test the hypothesis that fluxes in expression of HMGA2 pathway targets can be used as indices of LAM disease occurrence and severity. In the second aim of the study, we will further delineate the role of the HMGA2 pathway in the disease of LAM by determining if genetic and pharmacological disruption of the HMGA2 pathway disrupts growth and tumor formation in human iPS cells from LAM patients.

项目摘要 淋巴血管瘤瘤病（L​​AM）是一种进行性肺部疾病，可以导致呼吸衰竭和 潜在的死亡。 LAM用靶向雷帕霉素（MTOR）途径的哺乳动物靶标的药物治疗 但是，只有一部分患者对瞬时且无法治愈的治疗做出反应。有趣的是， 有许多研究表明，其他途径在 疾病。我们的实验室证明了高移动性组HMGA2，一种非固定染色体 建筑转录因子在LAM的发病机理中至关重要。我们小组的发表研究 证明hmga2是肺结核中间充质肿瘤发生所必需的（TSC2 +/-） 鼠标模型。因此，我们假设HMGA2信号通路驱动了 在LAM的TSC2单倍不使级状态下启动的肿瘤。此外，我们假设表达 HMGA2及其致癌途径基因的基因可用于LAM诊断和潜在预后。 为了检验我们的假设，我们提出以下目标：在第一个目标中，我们的研究将测试 假设HMGA2途径靶标的通量可以用作LAM疾病的指标 发生和严重性。在研究的第二个目标中，我们将进一步描述HMGA2的作用 通过确定HMGA2的遗传和药理学破坏，LAM疾病的途径 途径破坏了LAM患者的人IPS细胞的生长和肿瘤形成。