Patient-specific targeting of uterine fibroids

针对子宫肌瘤的患者特异性靶向治疗

基本信息

批准号：
10401333
负责人：
JOSE M. TEIXEIRA
金额：
$ 43.2万
依托单位：
MICHIGAN STATE UNIVERSITY
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：
2019-08-29 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10401333
关键词：
Address Affect African American Age Age of Onset Alternative Medicine Automobile Driving Benign Binding Bioinformatics Biological Assay Biological Markers Biometry Body mass index Cells ChIP-seq Characteristics Chromatin Chromosomal Instability Chromosomal Rearrangement Chromosome abnormality Common Neoplasm Complex DNA DNA Methylation DNA Sequence Alteration Data Data Analyses Development Disease Disease Management EZH2 gene Enantone Enhancers Ensure Epigenetic Process Ethnic Origin Etiology Exons Family Fertility Fibroid Tumor Gene Expression Gene Expression Profile Genes Genetic Transcription Genomics Gonadal Steroid Hormones Growth Growth and Development function HMGA2 gene Hormonal Human Hysterectomy In Vitro Incidence Knowledge Lead Location Mediator of activation protein Methylation Mus Mutate Mutation Myometrial Normal tissue morphology Onset of illness Pathway interactions Patients Population Population Characteristics Predisposing Factor Prevalence Proteins Race Recording of previous events Role Selective Estrogen Receptor Modulators Serum Severities Sterility Symptoms Therapeutic Tissues Transposase United States Uterine Fibroids Uterus Validation Woman Xenograft procedure aged associated symptom base caucasian American clinical care clinically significant cohort differential expression disabling symptom early onset effective therapy epigenomics exome sequencing experimental study genetic signature genome-wide genomic signature in vivo mutant myometrium new therapeutic target next generation sequencing overexpression parity periostin precision medicine programs racial disparity reproductive side effect targeted treatment tissue processing transcriptome sequencing

项目摘要

Project Summary Uterine leiomyomas (fibroids) are the most common tumors found in reproductive aged women, with an overall prevalence of up to 75% by age fifty. Patients with a clinically significant fibroid burden can have multiple debilitating symptoms, making fibroids the leading indication for hysterectomy in the United States. There is a strong racial disparity in the disease, with African-American women presenting with an earlier onset of the disease, with greater severity, and having a prevalence of 89% by the age of fifty. The etiology of the disease is largely unknown, but recent discoveries that the MED12 gene is mutated in 50-70% of fibroids and that introduction of a similar mutation in mouse uteri can lead to fibroids suggest that mutant MED12 may be a key player in the etiology of uterine fibroids. However, the actual mechanisms driving the disease, in either MED12 mutant fibroids or MED12 wildtype fibroids, are unknown. This gap in knowledge has hindered the development of effective therapies that obviate the need for women to have hysterectomies. We propose to exploit next generation sequencing to perform comprehensive analyses of the epigenetic, genomic, and transcriptional landscape of different subsets of uterine fibroids for comparison with normal myometria. We will also compare fibroids from caucasian and African-American women to try to understand the disparity in the disease between these two populations, which are not currently associated with any highly significant genetic mutations. We have assembled a team of experts for tissue processing and assays, next generation sequencing, and bioinformatic analyses and have performed preliminary studies that have led us to hypothesize that a fibroid subtype-specific precision medicine approach is needed for women with symptomatic disease. We will validate our preliminary results in a larger and more diverse cohort of women with greater depth and determine whether elevated serum levels of characteristic proteins we have determined are highly expressed in specific subsets of fibroids could be used as serum biomarkers for the disease. We will perform in vitro and in vivo experiments to understand the mechanisms and pathways disrupted by their overexpression. We will use the HumanMethylation (850k/EPIC) DNA methylation array to establish whether methylation differences among the fibroid subtypes contribute to the differential expression by RNA-seq. Chromatin immunoprecipitation sequencing (ChIP-Seq) will be done between MED12 mutant and HMGA2 overexpressing fibroids and myometrial cells to compare and contrast differential binding of these chromatin modifying proteins. We will use ATAC-seq to determine open chromatin regions in the tissues of the fibroid subtypes and correlate with RNA-seq. We will be analyzing both broad and deep data to provide a better understanding of combined RNA-seq, epigenetics, and genomic landscapes found in subsets of uterine fibroids. We expect that these studies will lead to development of patient-specific/precision medicine alternatives to hysterectomy for management of this disease.

项目概要子宫肌瘤（肌瘤）是育龄妇女中最常见的肿瘤，总体来说到 50 岁，患病率高达 75%。具有临床显着肌瘤负担的患者可能有多种使人衰弱的症状，使子宫肌瘤成为美国子宫切除术的主要适应症。有一个这种疾病的种族差异很大，非裔美国女性发病较早该病更为严重，到 50 岁患病率高达 89%。该病的病因学目前尚不清楚，但最近发现 50-70% 的肌瘤中 MED12 基因发生突变，并且在小鼠子宫中引入类似的突变会导致肌瘤，这表明突变的 MED12 可能是关键子宫肌瘤病因学的重要参与者。然而，在 MED12 中，驱动疾病的实际机制突变型肌瘤或 MED12 野生型肌瘤尚不清楚。这种知识上的差距阻碍了开发有效的疗法，使妇女无需进行子宫切除术。我们建议利用下一代测序对表观遗传、基因组和子宫肌瘤不同亚型的转录景观与正常子宫肌层进行比较。我们将还比较了白人和非裔美国女性的肌瘤，试图了解两者之间的差异这两个人群之间的疾病，目前与任何高度显着的遗传无关突变。我们组建了一个组织处理和分析专家团队，下一代测序和生物信息学分析并进行了初步研究，使我们假设有症状的女性需要针对肌瘤亚型的精准医疗方法疾病。我们将在更大、更多样化的女性群体中验证我们的初步结果。深度并确定我们确定的特征蛋白的血清水平是否高度升高在特定肌瘤亚群中表达的蛋白可用作该疾病的血清生物标志物。我们将表演体外和体内实验，以了解其破坏的机制和途径过度表达。我们将使用 HumanMmethylation (850k/EPIC) DNA 甲基化芯片来确定是否肌瘤亚型之间的甲基化差异导致 RNA-seq 的差异表达。将在 MED12 突变体和 HMGA2 之间进行染色质免疫沉淀测序 (ChIP-Seq) 过度表达肌瘤和子宫肌细胞，以比较和对比这些染色质的差异结合修饰蛋白质。我们将使用 ATAC-seq 来确定肌瘤组织中的开放染色质区域亚型并与 RNA-seq 相关。我们将分析广泛和深入的数据，以提供更好的了解子宫亚群中发现的组合 RNA-seq、表观遗传学和基因组景观肌瘤。我们期望这些研究将促进患者特异性/精准医学的发展治疗这种疾病的子宫切除术的替代方案。