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Med12 mechanisms of uterine leiomyoma formation

子宫肌瘤形成的 Med12 机制

基本信息

批准号：
10206208
负责人：
ALEKSANDAR RAJKOVIC
金额：
$ 32.14万
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/10206208
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.

摘要