Northwestern Uterine Leiomyoma Research Center

子宫肌瘤(LM，肌瘤)是女性最常见的肿瘤，尤其是非洲人- ，并导致不规则子宫出血和贫血，需要20多万例子宫切除术 每年在美国。我们的长期目标是了解新的临床相关和医学目标 子宫肌萎缩侧索硬化症的发病机制及生长机制 发病率。我们建议并申请资金支持西北子宫肌瘤研究 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因素体细胞突变(mut-)或重排 (-ra)影响MED12和HMGA2基因在85%的LM中被发现，但潜在的 导致肿瘤发生和肿瘤生长的机制尚不清楚。我们建议确定影响 MUT-MED12和HMGA2-ra对LM细胞表观基因组编程、LSC功能的影响 这些肿瘤中异基因细胞群体的发展，以及全基因组孕酮(P4)的作用。我们 将使用尖端的活体模型和高通量技术来揭示新的机制和 确定针对特定基因型的治疗目标，以开发精准的LM医疗治疗方法。项目1 (Bulun/Yen/Dai)将测试mut-MED12改变全基因组孕激素受体(PR)的假设- 染色质相互作用信号和相关的组蛋白修饰，从而增强Lm中P4的作用 中间细胞群(LICs)，为LSC的存活和增殖提供支持。项目2 (Rajkovic)将测试影响MED12和HMGA2的不同驱动程序突变决定细胞 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 Lm.项目3(Chakravarti/wei)将测试在LM中过表达HMGA2会改变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.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- 子宫组织内含MUT-MED12的等效性LM小鼠模型。教育和外展的核心意志 通过发展沟通、外联、支持中心内部和跨中心的研究活动 和教育战略，以促进卫生公平和消除土地管理方面的差距，吸引普通公众， 芝加哥地区的学生，以及科学和医学界。行政核心将确保 该中心实现了其目标，并将使个别研究项目与 教育--外联核心和其他机构核心；它还将征求和协调对试点项目的审查 项目。我们预计我们的协同方法将导致突变或表观遗传学的发展。 签名-选择治疗方法的LM，将该领域移动到个性化医学领域。

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.