Med12 mechanisms of uterine leiomyoma formation

子宫肌瘤形成的 Med12 机制

基本信息

批准号：
9697630
负责人：
ALEKSANDAR RAJKOVIC
金额：
$ 32.83万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9697630
关键词：
Abnormal Karyotype Address Age American Amino Acids Centers for Disease Control and Prevention (U.S.)Chromosomal Rearrangement Chromosome Breakage Clinical DNA Binding Data Development Enhancers Exons Fibroid Tumor Gene Expression Genetic Genetic Epistasis Genetic Transcription Genomic Instability Genomics Glycine Growth Health Care Costs Hormonal Human Human Pathology Hysterectomy Lead Leiomyoma Lesion Mesenchymal Mesenchyme Modeling Molecular Morbidity - disease rate Mus Mutate Mutation Nucleotides Operative Surgical Procedures Pathology Pathway interactions Play Population Heterogeneity Prevalence Proteins Public Health Rest Role Smooth Muscle Steroids TSC2 gene Testing Tissues Transcriptional Regulation Uterine Fibroids Uterine Neoplasms Uterus Variant Woman beta catenin cell type clinical Diagnosis comparative genomic hybridization dosage endometrial stroma exome sequencing gain of function gain of function mutation genomic profiles insight leiomyosarcoma loss of function mouse model myometrium novel overexpression racial diversity reproductive reproductive function transcriptome tumor tumor growth tumorigenesis

项目摘要

Abstract Uterine leiomyomas, better known as fibroid tumors, are clinically apparent in almost 25% of women and cause major morbidity to American women with almost 200,000 surgeries performed to either remove the leiomyoma tumors or the whole uterus (hysterectomy). Ours and other groups have utilized whole exome sequencing to identify exon 2 of MED12 as a hotspot of mutations in leiomyomas. Our study on racially diverse population of American women showed that Med12 exon 2 was mutated in 100/148 leiomyomas (67%). The most common human MED12 mutation among leiomyomas of American women is a non-synonymous variant, c.131G>A, predicted to substitute a highly conserved glycine with aspartic amino acid (p.Gly44Asp). We generated novel mouse models that showed leiomyoma formation in the presence of Med12 c.131G>A nucleotide variant. The onset of tumor formation was earlier and the size of these tumors was larger when Med12 c.131G>A nucleotide variant was expressed on Med12 deficient uterine mesenchymal background. Conditional deficiency of Med12 in uterine mesenchyme did not lead to tumor formation. Our preliminary data is consistent with Med12 c.131G>A nucleotide variant acting via a gain of function genetic mechanism. In the current proposal we will build upon our preliminary studies to further understand molecular mechanisms behind Med12 c.131G>A nucleotide variant induced pathology, genomic imbalances and how Med12 c.131G>A nucleotide variant interacts with previously implicated pathways in leiomyoma formation, such as beta-catenin, REST and GPR10. The three aims in our proposal will test the following hypotheses: 1) Med12 c.131G>A nucleotide variant is a hormonally responsive gain of function mutation and interacts synergistically with other pathways implicated in leiomyoma formation, 2) Med12 c.131G>A nucleotide variant disrupts DNA binding and overall gene expression with disruption confined via tissue specific mechanisms to the myometrium and 3) Med12 c.131G>A nucleotide variant drives genomic instability observed in leiomyomas via a common set of recurring genomic imbalances. The focus on Med12 and its role in reproductive function is of great importance given recent human studies showing its association in uterine leiomyomas, including poorly understood leiomyosarcomas. We have successfully generated a mouse model of Med12 mutation that results in impressive leiomyomas and replicates well the human condition. We will use this model to better understand mechanisms behind the Med12 actions in leiomyoma formation.

抽象的子宫肌瘤（俗称纤维瘤）在临床上在近 25% 的女性中表现明显并给美国女性带来了严重的发病率，近 200,000 例手术中的任何一个都进行了切除平滑肌瘤或整个子宫（子宫切除术）。我们和其他团体有利用全外显子组测序将 MED12 的外显子 2 识别为突变热点平滑肌瘤。我们对美国女性种族多样化人群的研究表明，Med12 外显子 2 100/148 的平滑肌瘤 (67%) 中发生突变。最常见的人类 MED12 突变美国女性的平滑肌瘤是一种非同义变异，c.131G>A，预计将取代高度保守的甘氨酸与天冬氨酸 (p.Gly44Asp)。我们生成了新颖的小鼠模型显示在 Med12 c.131G>A 核苷酸变体存在的情况下平滑肌瘤的形成。发病当 Med12 c.131G>A 时，肿瘤形成较早且肿瘤尺寸较大核苷酸变异体在 Med12 缺陷子宫间充质背景下表达。有条件的子宫间质中 Med12 的缺乏不会导致肿瘤形成。我们的初步数据是与 Med12 c.131G>A 核苷酸变体一致，通过功能获得遗传机制发挥作用。在当前的提案中，我们将在初步研究的基础上进一步了解分子 Med12 c.131G>A 核苷酸变异诱发病理、基因组失衡背后的机制以及 Med12 c.131G>A 核苷酸变体如何与之前涉及的通路相互作用平滑肌瘤形成，例如 β-连环蛋白、REST 和 GPR10。我们提案中的三个目标将测试以下假设：1) Med12 c.131G>A 核苷酸变异是激素响应增益功能突变并与平滑肌瘤涉及的其他途径协同相互作用形成，2) Med12 c.131G>核苷酸变异破坏 DNA 结合和整体基因表达通过组织特异性机制限制子宫肌层的破坏和 3) Med12 c.131G>A 在平滑肌瘤中观察到的核苷酸变异通过一组常见的重复性驱动基因组不稳定性基因组失衡。关注 Med12 及其在生殖功能中的作用非常重要鉴于最近的人类研究表明其与子宫肌瘤的关联，包括不良了解平滑肌肉瘤。我们已成功生成 Med12 突变小鼠模型这会产生令人印象深刻的平滑肌瘤，并很好地复制了人类的状况。我们将使用这个模型更好地了解 Med12 在平滑肌瘤形成中作用背后的机制。