Northwestern Uterine Leiomyoma Research Center

西北子宫肌瘤研究中心

• 批准号: 10153840
• 负责人: Serdar E. Bulun
• 金额: $ 146.67万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10153840
• 关键词: 3-Dimensional; Affect; African American; Anemia; Antibodies; Area; Awareness; Biological Models; Cell Culture Techniques; Cell Proliferation; Cells; Chicago; Chromatin; Common Neoplasm; Communication; Communities; Community Outreach; Development; Education; Education and Outreach; Ensure; Environment; Epigenetic Process; Fibroid Tumor; Funding; Future; General Population; Genomics; Genotype; Goals; Growth; Gynecologic; HMGA2 gene; Health; Heterogeneity; Human; Hysterectomy; Individual; Infrastructure; Medical; Molecular; Morbidity - disease rate; Mutation; Pathogenesis; Pathologist; Pilot Projects; Population; Pregnancy loss; Process; Progesterone; Progesterone Receptors; Public Health; Recurrence; Research; Research Activity; Research Personnel; Research Project Grants; Research Support; Running; Sampling; Science; Somatic Mutation; Structure; Students; Testing; Therapeutic; Tissue Procurements; Tissue Sample; Tissues; Translational Research; Uterine Fibroids; Uterine hemorrhage; Uterus; Woman; Work; Yin; base; cancer genome; career; cell preparation; clinically relevant; design; disparity elimination; driver mutation; epigenome; epigenomics; experience; flexibility; genome-wide; health equity promotion; high throughput technology; histone modification; human tissue; in vivo Model; minority student; mouse model; myometrium; novel; novel therapeutics; outreach; overexpression; personalized medicine; programs; reproductive; stem cell function; stem cell survival; therapeutic target; treatment response; tumor growth; tumor initiation; tumorigenesis; underserved students

Uterine leiomyoma (LM, fibroids) are the most common tumor in women, disproportionately affect African- Americans, and cause irregular uterine bleeding and anemia, necessitating more than 200,000 hysterectomies annually in the US. Our long-term objective is to understand novel clinically relevant and medically targetable mechanisms responsible for the pathogenesis and growth of uterine LM in order to reduce associated morbidity. We propose and request funds to support the Northwestern Uterine Leiomyoma Research Center, comprising three highly coordinated and synergistic Research Projects, an Administrative Core and an Education and Outreach Core. Two mutually exclusive key driver somatic mutations (mut-) or rearrangements (-ra) affecting the MED12 and HMGA2 genes have been found in 85% of all LM, but the underlying mechanisms that cause tumorigenesis and tumor growth remain unknown. We propose to ascertain the effects of mut-MED12 and HMGA2-ra on epigenomic programming of LM cells, LM stem cell (LSC) function, development of heterogenic cell populations in these tumors, and genome-wide progesterone (P4) action. We will use cutting-edge in vivo models and high-throughput technologies to uncover novel mechanisms and identify genotype-specific therapeutic targets for developing precision medical treatments for LM. Project 1 (Bulun/Yin/Dai) will test the hypothesis that mut-MED12 alter genome-wide progesterone receptor (PR)- chromatin interaction signatures and associated histone modifications, thereby enhancing P4 action in the LM intermediate cell population (LICs), which provides a support niche for LSC survival and proliferation. Project 2 (Rajkovic) will test the hypothesis that distinct driver mutations affecting MED12 and HMGA2 determine cellular and molecular heterogeneity during LM tumorigenesis. Through cell fate tracing studies, we will determine whether mut-MED12 cells give rise to different cell populations in the myometrium that drive the formation of LM. Project 3 (Chakravarti/Wei) will test the hypothesis that overexpression of HMGA2 in LM alters 3D chromatin interactions and the epigenome to modify the development, progression, and therapeutic response of LM. As model systems, we will use LM tissues, antibody-sorted human LM cell populations and a human- equivalent mouse model of LM with mut-MED12 in uterine tissue. The Education and Outreach Core will support research activities performed within and across the Center by developing communication, outreach, and education strategies to promote health equity and eliminate disparities in LM, engaging the general public, students in the Chicago area, and the scientific and medical community. The Administrative Core will ensure that the Center achieves its aims and will synergize the individual Research Projects with the work of the Education-Outreach Core and other institutional cores; it will also solicit and coordinate the review of Pilot Projects. We anticipate that our synergistic approach will lead to the development of mutation- or epigenetic signature-selective therapeutic approaches to LM, moving the field into the realm of personalized medicine.

子宫肌瘤（LM，肌瘤）是女性最常见的肿瘤，不成比例地影响非洲- 美国人，导致不规则子宫出血和贫血，需要超过 200,000 例子宫切除术 每年在美国。我们的长期目标是了解新颖的临床相关且具有医学针对性的药物 负责子宫 LM 发病机制和生长的机制，以减少相关 发病率。我们提议并请求资金支持西北子宫平滑肌瘤研究 中心，由三个高度协调和协同的研究项目、一个行政核心和一个 教育和外展核心。两个相互排斥的关键驱动体细胞突变 (mut-) 或重排 (-ra) 在 85% 的 LM 中发现了影响 MED12 和 HMGA2 基因的因素，但潜在的 导致肿瘤发生和肿瘤生长的机制仍不清楚。我们建议确定影响 mut-MED12 和 HMGA2-ra 对 LM 细胞的表观基因组编程、LM 干细胞 (LSC) 功能、 这些肿瘤中异质细胞群的发育以及全基因组黄体酮（P4）的作用。我们 将使用尖端的体内模型和高通量技术来揭示新的机制和 确定基因型特异性治疗靶点，以开发针对 LM 的精准医疗。项目1 (Bulun/Yin/Dai) 将测试 mut-MED12 改变全基因组孕酮受体 (PR) 的假设 - 染色质相互作用特征和相关组蛋白修饰，从而增强 LM 中的 P4 作用 中间细胞群（LIC），为 LSC 的生存和增殖提供支持。项目2 （Rajkovic）将检验以下假设：影响 MED12 和 HMGA2 的不同驱动突变决定细胞 LM肿瘤发生过程中的分子异质性。通过细胞命运追踪研究，我们将确定 mut-MED12 细胞是否在子宫肌层中产生不同的细胞群，从而驱动形成 LM。项目 3 (Chakravarti/Wei) 将测试 LM 中 HMGA2 过度表达改变 3D 的假设 染色质相互作用和表观基因组改变发育、进展和治疗反应 LM 的。作为模型系统，我们将使用 LM 组织、抗体分选的人类 LM 细胞群和人类 子宫组织中含有 mut-MED12 的 LM 等效小鼠模型。教育和外展核心将 通过发展沟通、外展、 和教育战略，以促进健康公平并消除LM中的差异，吸引公众参与， 芝加哥地区的学生以及科学和医学界。行政核心将确保 该中心实现其目标并将使各个研究项目与该中心的工作产生协同作用 教育外展核心和其他机构核心；它还将征求并协调试点的审查 项目。我们预计我们的协同方法将导致突变或表观遗传的发展 LM 的特征选择性治疗方法，将该领域带入个性化医疗领域。