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.

项目摘要子宫平滑肌瘤（肌瘤）是生殖老年妇女中最常见的肿瘤，总体到五十岁时的患病率高达75％。具有临床意义的肌瘤负担的患者可能有多个使症状衰弱，使肌瘤成为美国子宫切除术的主要指标。有一个这种疾病的种族差异很大，非裔美国妇女呈现早期的发作疾病，严重程度更高，到五十岁时患病率为89％。疾病的病因在很大程度上未知，但是最近发现Med12基因在50-70％的肌瘤中被突变，并且引入小鼠子宫中类似突变的可能导致肌瘤表明突变体Med12可能是钥匙子宫肌瘤病因学的球员。但是，在任何一种MED12中，驱动疾病的实际机制突变肌瘤或Med12野生型肌瘤是未知的。知识的差距阻碍了开发有效的疗法，以消除妇女需要子宫切除术的需求。我们建议利用下一代测序以对表观遗传，基因组和子宫肌瘤的不同子集的转录景观与正常肌亚三分。我们将还要比较来自白种人和非裔美国妇女的肌瘤，以尝试了解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。我们已经组建了一个专家团队进行组织处理和测定，下一代测序和生物信息学分析并进行了初步研究，使我们得以实现假设有症状的女性需要一种肌瘤亚型特异性的精确药物方法疾病。我们将在更大，更多样化的女性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高在特定的肌瘤亚群中表达，可以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表达。我们将使用人甲基化（850K/EPIC）DNA甲基化阵列来确定是否是否肌瘤亚型之间的甲基化差异有助于RNA-Seq的差异表达。染色质免疫沉淀测序（CHIP-SEQ）将在Med12突变体和HMGA2之间进行过表达的肌瘤和肌层细胞以比较和对比差异结合这些染色质修饰蛋白质。我们将使用ATAC-SEQ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度数据，以提供更好的了解在子宫中发现的RNA-seq，表观遗传学和基因组景观肌瘤。我们预计这些研究将导致患者特异性/精度医学的发展子宫切除术的替代方法用于治疗该疾病。