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 淋巴管平滑肌瘤病（LAM）是一种进行性肺部疾病，可导致呼吸衰竭， 潜在的死亡LAM用靶向雷帕霉素（mTOR）通路的哺乳动物靶标的药物治疗 然而，只有一小部分病人对治疗有反应，这是短暂的，不能治愈。有趣的是， 有许多研究表明，其他途径是重要的发病机制， 这种疾病我们的实验室已经证明，高迁移率族HMGA 2，一个非组蛋白的染色体 结构转录因子在LAM的发病机制中至关重要。我们小组发表的研究 证明HMGA 2是结节性硬化症（Tsc 2 +/-）间充质肿瘤发生所必需的 小鼠模型因此，我们假设HMGA 2信号通路驱动了 在LAM中肿瘤起始于TSC 2单倍不足状态。此外，我们假设表达式 HMGA 2及其致癌通路基因的表达可用于LAM的临床诊断和潜在预后。 为了检验我们的假设，我们提出了以下目标：在第一个目标，我们的研究，我们将测试 HMGA 2通路靶点表达通量可用作LAM疾病指标的假设 发生率和严重程度。在本研究的第二个目的中，我们将进一步阐明HMGA 2的作用。 通过确定HMGA 2的遗传和药理学破坏， 在来自LAM患者的人iPS细胞中，该途径破坏了生长和肿瘤形成。