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（UFS）是肌层中产生的单克隆肿瘤，是最多的生殖年龄妇女的常见肿瘤。越来越多的证据支持假设UFS起源于肌层中异常干细胞。我们现在已经确定了 stro-1+/CD44+肌层干细胞（MSC），能够自我再生和再生肌层组织，在动物模型中引起UFS。我们有能力识别和隔离这些MSC，我们处于独特的位置，可以解决风险因素如何影响UF 原生素启动和促进这些肿瘤的发育。像许多疾病一样，有充分的证据表明环境暴露和遗传改变有助于UF发病机理。我们和其他人已经表明了早期的生活环境暴露于内分泌破坏化合物（EDC）通过诱导表观基因组的发育重编程。这种表观基因组重编程涉及改变染色质结构和的组蛋白和DNA甲基化模式基因转录，并在早期诱发时，一直持续到成年。遗传改变介体12（MED12）和结节硬化症复合物2（TSC2）肿瘤抑制剂，驱动器分别在人类和啮齿动物模型中开发UF肿瘤。有趣的是，Med12 TSC2缺陷共享一个常见的下游效应子：β-catenin信号传导的激活和基因表达的TCF/LEF反式激活。我们以前无法询问UF的原始单元，这限制了我们对基因：环境相互作用（GXE）影响UF风险。现在我们可以隔离和配置 MSC，我们第一次可以克服理解的关键障碍这种重要疾病的风险决定因素。在此应用程序中，我们将利用我们的新发现能够隔离和询问MSC，并应用有关环境的最新见解暴露于重新编程表观基因组，以探索促进的GXE相互作用 UFS的原始细胞中的肿瘤发生。特定目标1：检验β-catenin信号的激活是一种常见的假设驱动UFS的遗传改变的效应途径。在这个机械目标中，我们将测试在MSC中，MED12突变（人）或TSC2（大鼠）丧失的假设导致改变转录谱为特征是基因表达的TCF/LEF反式激活增加。特定目的2：检验以下假设：发育EDC暴露会导致表观遗传重新编程，该教练在MSC/TICS中具有遗传缺陷。在这个机械目标中，我们将表征EDC诱导的表观基因组的重编程，并检验以下假设。当β-catenin为在RMSC和肿瘤引发的细胞（TICS）中激活。特定目标3：检验与高vs低UF风险相关的MSC的假设表观遗传组蛋白修饰的差异。在这个翻译目标中，我们将探索使用从正常的MSC进行的MSC表观遗传模式与UF风险之间的关系女性的女性（MYON）和UFS女性的高风险子宫肌的子宫肌层（Myof）。由于表观基因质的改变可能是可逆的，因此我们还将测试假设降低UF风险的干预措施通过减少MSC数量和/或 “重置” MSC表观基因组回到低风险状况。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;妇科健康和疾病中的茎/祖细胞，跨学科研究和妇科疾病中的“ –omics”。重要的是，这也将是GXE的第一次探索在UFS原始细胞中驱动疾病的相互作用。