The Origin and Cellular Heterogeneity of Uterine Leiomyomas

子宫肌瘤的起源和细胞异质性

基本信息

批准号：
10613377
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
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10613377
关键词：
Accounting Affect Age American Amino Acids Anemia Automobile Driving Benign Cell Communication 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 Medical Molecular Morbidity - disease rate Mus Mutation Nature Operative Surgical Procedures Pain Pathway interactions Patients Pelvis 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 exome in vivo insight molecular phenotype mouse model mutant myometrium novel diagnostics novel therapeutic intervention overexpression pharmacologic pressure prevent reproductive single cell sequencing targeted treatment transcriptome tumor uterine smooth muscle cell

项目摘要

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.

子宫肌瘤的药物治疗因我们对子宫肌瘤的了解有限而受到阻碍。这些肿瘤的起源和进化，以及分子异质性程度。平滑肌瘤也肌瘤是子宫平滑肌细胞最常见的良性肿瘤，是一种主要的子宫肌瘤。美国女性发病的原因。先前的研究表明肌瘤是起源于单克隆。然而，平滑肌瘤的组织学和细胞分选分析表明，细胞异质性，除了平滑肌细胞外，平滑肌瘤肿瘤中还存在成纤维细胞。我们小组和其他人的全外显子组方法已经确定了介导复合物中的突变大约 70% 的 LM 患者存在亚基 12 (MED12)，表明 MED12 突变细胞可能会产生上升为平滑肌瘤。我们建立了一个小鼠模型，显示子宫内平滑肌瘤的形成表达 Med12 突变。我们将利用我们的小鼠模型开始研究平滑肌瘤的早期起源并与该 P50 应用程序的其他项目进行交互，以定义平滑肌瘤的分子异质性及其与肿瘤基因型的关系。我们的研究将集中于：1）了解发病和 Med12 突变阳性平滑肌瘤的进展，2) 子宫基因组不稳定性的演变平滑肌瘤，3) 了解平滑肌瘤基因型与分子水平之间的关系可能影响平滑肌瘤复发率和对治疗无反应的异质性。我们的小鼠模型和初步结果将补充本 P50 中其他研究人员的研究应用。我们将为 Bulun 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我们自己在小鼠和人类中进行的研究表明平滑肌瘤细胞类型。 Chakravarti博士的项目3将受益来自我们对 MED12 阳性、HMGA2 阳性和 MED12/HMGA2 阴性的单细胞测序平滑肌瘤，并将补充他对 HMGA2 阳性平滑肌瘤的表观遗传学研究。在一起，我们和我们的合作者提出的研究将为病理生理学提供深入的见解子宫LM。我们的研究将确定 Med12 阳性平滑肌瘤的起源，确定基因型是否驱动分子表型和细胞异质性，目标是推动平滑肌瘤的靶向治疗。