Gene X Environment Interactions in the Pathogenesis of Uterine Fibroids

子宫肌瘤发病机制中 X 基因环境相互作用

基本信息

批准号：
10286273
负责人：
Ayman Al-Hendy
金额：
$ 35.59万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-11-11 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10286273
关键词：
Address Adult African American Age Animal Model Architecture Area Back Benign CD44 gene Caucasians Cell Count Cells ChIP-seq Chromatin Common Neoplasm DNA Methylation Defect Development Disease Endocrine Disruptors Environmental Exposure Epigenetic Process Ethnic Origin Etiology Exhibits Exposure to Fibroid Tumor Gene Expression Genes Genetic Transcription Goals Gynecologic Health Healthcare Histone H3 Histones Human Hysterectomy Immunohistochemistry Intervention Investigation Knowledge Leiomyoma Life Link Lysine Mediator of activation protein Mutation Myometrial Natural regeneration Pathogenesis Pathway interactions Pattern Positioning Attribute Preventive Race Rattus Research Research Priority Risk Risk Factors Rodent Model Role Signal Transduction Testing Time Tissues Transactivation Tuberous sclerosis protein complex Tumor Stem Cells Tumor Suppressor Proteins United States National Institutes of Health Uterine Fibroids Woman Women&apos s Health Work beta catenin epigenome epigenomics gene environment interaction histone methylation histone modification human model insight methylation pattern myometrium neoplastic neoplastic cell novel therapeutics reproductive system neoplasm response self-renewal stem stem cells transcriptome sequencing tumor tumorigenesis

项目摘要

Abstract Uterine Fibroids (UFs) are monoclonal tumors arising in the myometrium, and are the most common tumor of reproductive age women. An increasing body of evidence supports the hypothesis that UFs originate from aberrant stem cells in the myometrium. We have now identified a Stro-1+/CD44+ myometrial stem cell (MSC) capable of self-renewal and regeneration of myometrial tissues, which gives rise to UFs in animal models. With our ability to identify and isolate these MSCs, we are in a unique position to address how risk factors impact the UF cell-of-origin to initiate and promote the development of these tumors. Like many diseases, there is ample evidence that both environmental exposures and genetic alterations contribute to UF pathogenesis. We, and others have shown that early life environmental exposures to endocrine disrupting compounds (EDCs) increase UF risk by inducing developmental reprogramming of the epigenome. Such epigenomic reprogramming involves changes in histone and DNA methylation patterns that alter chromatin architecture and gene transcription, and when induced in early life, persist into adulthood. Genetic alterations in mediator 12 (MED12) and the tuberous sclerosis complex 2 (TSC2) tumor suppressor, drive development of UF tumors in both humans and rodent models, respectively. Interestingly, MED12 and TSC2 defects share a common downstream effector: activation of β-catenin signaling and TCF/LEF transactivation of gene expression. Our previous inability to interrogate the cells-of-origin for UFs has limited our understanding of how gene:environment interactions (GxE) influence UF risk. Now that we can isolate and profile MSCs, we are for the first time in a position to overcome this critical barrier to understanding determinants of risk for this important disease. In this application we will utilize our new-found ability to isolate and interrogate MSCs, and apply recent insights on how environmental exposures reprogram the epigenome, to explore GxE interactions that promote tumorigenesis in the cell-of-origin for UFs. Specific Aim 1: Test the hypothesis that activation of β-catenin signaling is a common effector pathway for genetic alterations that drive UFs. In this mechanistic Aim, we will test the hypothesis that in MSCs, MED12 mutation (human) or loss of Tsc2 (rat) results in an altered transcriptional profile characterized by increased TCF/LEF transactivation of gene expression. Specific Aim 2: Test the hypothesis that developmental EDC exposure results in epigenetic reprogramming that cooperates with genetic defects in MSC/TICs. In this mechanistic Aim, we will characterize EDC-induced reprogramming of the epigenome, and test the hypothesis that reprogramming of TCF/LEF target genes exacerbates their expression when β-catenin is activated in rMSCs and in tumor initiating cells (TICs). Specific Aim 3: Test the hypothesis that MSCs associated with high vs low UF risk exhibit differences in epigenetic histone modifications. In this translational Aim, we will explore the relationship between MSC epigenetic patterns and UF risk using MSCs isolated from normal myometrium of women without UFs (MyoN) and at-risk myometrium from women with UFs (MyoF). Because epigenomic alterations are potentially reversable, we will also test the hypothesis that an intervention that reduces UF risk does so by decreasing MSC number and/or “resetting” the MSC epigenome back to a low risk profile. Impact: Our work address several knowledge gaps and priority research areas as defined by NIH including; Stem/Progenitor Cells in Gynecologic Health and Disease, Transdisciplinary Research and '–Omics' in Gynecologic Disorders. Importantly, it will also be the first exploration of GxE interactions that drive disease in the cells of origin for UFs.

抽象的子宫肌瘤（UF）是起源于子宫肌层的单克隆肿瘤，是最常见的单克隆肿瘤。越来越多的证据支持育龄妇女的常见肿瘤。我们现在已经鉴定出 UF 源自子宫肌层中的异常干细胞的假设。 Stro-1+/CD44+ 子宫肌层干细胞 (MSC) 能够自我更新和再生子宫肌组织，在动物模型中产生 UF，我们有能力识别和确定。隔离这些 MSC，我们处于独特的地位来解决风险因素如何影响 UF 源细胞启动并促进这些肿瘤的发展。与许多疾病一样，有充分的证据表明环境暴露和遗传因素我们和其他人已经证明，早期生命的改变有助于 UF 发病机制。环境中暴露于内分泌干扰化合物 (EDC) 会增加 UF 风险诱导表观基因组的发育重编程。涉及组蛋白和 DNA 甲基化模式的变化，从而改变染色质结构和基因转录在生命早期被诱导，会持续到成年期。介质 12 (MED12) 和结节性硬化症复合体 2 (TSC2) 肿瘤抑制因子、驱动器分别在人类和啮齿动物模型中发展UF肿瘤。和 TSC2 缺陷共享一个共同的下游效应器：β-catenin 信号传导的激活和 TCF/LEF 基因表达反式激活。我们之前无法询问超滤细胞的起源，这限制了我们对超滤的理解。基因：环境相互作用 (GxE) 如何影响 UF 风险现在我们可以分离和分析。 MSC，我们第一次能够克服这一理解的关键障碍在此应用中，我们将利用我们新发现的风险决定因素。分离和询问 MSC 的能力，并应用关于环境如何影响的最新见解暴露重新编程表观基因组，探索 GxE 相互作用，促进 UF 细胞起源的肿瘤发生。具体目标 1：检验 β-连环蛋白信号传导激活是一种常见现象的假设驱动 UF 的基因改变的效应途径。在这个机械目标中，我们将测试。假设在 MSC 中，MED12 突变（人类）或 Tsc2 缺失（大鼠）会导致转录谱的特征是基因表达的 TCF/LEF 反式激活增加。具体目标 2：检验发育性 EDC 暴露导致表观遗传的假设与 MSC/TIC 中的遗传缺陷相配合的重编程在此机制目标中，我们将描述 EDC 诱导的表观基因组重编程，并检验以下假设：当 β-catenin 被破坏时，TCF/LEF 靶基因的重编程会恶化其表达在 rMSC 和肿瘤起始细胞 (TIC) 中激活。具体目标 3：检验 MSC 与高和低 UF 风险相关的假设在这个翻译目标中，我们将探讨表观遗传组蛋白修饰的差异。使用从正常人中分离的 MSC 观察 MSC 表观遗传模式与 UF 风险之间的关系没有 UF 的女性 (MyoN) 的子宫肌层和患有 UF 的女性的高危子宫肌层 (MyoF)。因为表观基因组改变可能是可逆的，所以我们还将测试假设降低 UF 风险的干预措施是通过减少 MSC 数量和/或将 MSC 表观基因组“重置”至低风险状况。影响：我们的工作解决了 NIH 定义的几个知识差距和优先研究领域包括；干/祖细胞在妇科健康和疾病中的跨学科研究重要的是，这也将是 GxE 的首次探索。导致 UF 起源细胞疾病的相互作用。