The Origin and Cellular Heterogeneity of Uterine Leiomyomas

子宫肌瘤的起源和细胞异质性

• 批准号: 10153843
• 负责人: ALEKSANDAR RAJKOVIC
• 金额: $ 44.21万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10153843
• 关键词: Accounting; Affect; Age; American; Amino Acids; Anemia; Automobile Driving; Benign; Cell Separation; Cells; Cellular Leiomyoma; Clonal Expansion; Complement; Complex; DNA Sequence Alteration; Data; Development; Disease; Disease Progression; Epigenetic Process; Evolution; Fibroblasts; Fibroid Tumor; Functional disorder; Gene Expression Profile; Gene Mutation; Genes; Genetic; Genetic study; Genomic Instability; Genotype; Glycine; Goals; HMGA2 gene; Heterogeneity; Histologic; Human; Human Pathology; Hysterectomy; Individual; Knowledge; Label; Leiomyoma; Mediator of activation protein; Medical; Molecular; Morbidity - disease rate; Mus; Mutation; Nature; Operative Surgical Procedures; Pain; Pathway interactions; Patients; Pelvis; Pharmacology; Population; Premature Birth; Progesterone; Recurrence; Reporting; Research; Research Personnel; Research Project Grants; Role; Sampling; Smooth Muscle Myocytes; Testing; Uterine Fibroids; Uterine Neoplasms; Uterine myomectomy; Uterus; Variant; Woman; Work; cell type; cohesion; exome; in vivo; insight; molecular phenotype; mouse model; mutant; myometrium; novel diagnostics; novel therapeutic intervention; overexpression; pressure; prevent; reproductive; single cell sequencing; targeted treatment; transcriptome; tumor; uterine smooth muscle cell

Pharmacologic therapies for uterine leiomyomas are hampered by our limited knowledge regarding the origin and evolution of these tumors, as well as the degree of molecular heterogeneity. Leiomyomas, also known as fibroids, are the most common benign tumors of uterine smooth muscle cells and are a major cause of morbidity among American women. Previous studies have suggested that fibroids are monoclonal in origin. However, histological and cell sorting analyses of leiomyomas have shown cellular heterogeneity, with presence of fibroblasts in addition to the smooth muscle cells in leiomyoma tumours. Whole exome approaches from our group and others have identified mutations in the mediator complex subunit 12 (MED12) in approximately 70% of LM patients, indicating that MED12 mutant cells might give rise to leiomyomas. We generated a mouse model that showed leiomyoma tumor formation in uteri that express Med12 mutation. We will utilize our mouse models to begin the study of leiomyoma early origins and interact with other Projects of this P50 application, to define molecular heterogeneity of leiomyomas and their relation to the tumor genotype. Our studies will focus to: 1) understand the onset and progression of Med12 mutation positive leiomyomas, 2) the evolution of genomic instability in uterine leiomyomas, and 3) understand the relationship between leiomyoma genotype and molecular heterogeneity that may impact leiomyoma recurrence rates and non-responsiveness to therapy. Our mouse model and preliminary findings will complement studies of other investigators in this P50 application. We will provide Dr. Bulun's Project 1 with our mouse model and in vivo preliminary data that Med12 interacts with the progesterone pathway, as well as complement his studies on different human leiomyoma cell types with our own studies in mice and humans. Dr. Chakravarti's Project 3 will benefit from our single cell sequencing on MED12 positive, HMGA2 positive, and MED12/HMGA2 negative leiomyomas and will complement his epigenetic studies on HMGA2 positive leiomyomas. Together, the studies proposed by us and our collaborators will provide great insights into the pathophysiology of uterine LM. Our studies will identify origin of Med12 positive leiomyomas, determine if genotype drives molecular phenotype and cellular heterogeneity, with a goal of driving targeted therapy for leiomyomas.

由于我们对子宫肌瘤的了解有限，子宫肌瘤的药物治疗受到阻碍。 这些肿瘤的起源和演化，以及分子的异质性程度。肌瘤，也是 肌瘤是子宫平滑肌细胞中最常见的良性肿瘤，是一种主要的 导致美国女性患病的原因。此前的研究表明，肌瘤是 起源于单克隆性。然而，肌瘤的组织学和细胞分选分析显示细胞 肌瘤中除平滑肌细胞外，还有成纤维细胞的异质性。 我们小组和其他人的整个外显子组方法已经确定了介体复合体的突变 在大约70%的LM患者中存在12亚单位(MED12)，这表明MED12突变细胞可能会 上升为肌瘤。我们建立了一个小鼠模型，显示子宫中肌瘤的形成 表达MED12突变。我们将利用我们的小鼠模型开始研究肌瘤的早期起源。 并与P50应用的其他项目相互作用，以确定肌瘤的分子异质性 以及它们与肿瘤基因的关系。我们的研究将集中在：1)了解疾病的发病和 MED12基因突变阳性子宫肌瘤的研究进展2)子宫基因组不稳定性的演变 3)了解子宫肌瘤基因分型与分子水平的关系。 可能影响肌瘤复发率和治疗无反应的异质性。我们的 小鼠模型和初步发现将补充本P50中其他研究人员的研究 申请。我们将向布伦博士的项目1提供我们的小鼠模型和体内初步数据 MED12与孕酮途径相互作用，并补充了他对不同人类的研究 与我们自己在老鼠和人类身上的研究相结合的平滑肌瘤细胞类型。查克拉瓦蒂博士的项目3将受益 从我们的单细胞测序来看，MED12阳性，HMGA2阳性，MED12/HMGA2阴性 并将补充他对HMGA2阳性肌瘤的表观遗传学研究。团结在一起， 我们和我们的合作者提出的研究将为我们提供对脑血管疾病病理生理学的深刻见解 子宫肌层析。我们的研究将确定MED12阳性肌瘤的来源，确定基因是否驱动 分子表型和细胞异质性，目标是推动肌瘤的靶向治疗。