Northwestern Uterine Leiomyoma Research Center

子宫平滑肌瘤（LM，纤维瘤）是女性最常见的肿瘤，不成比例地影响非洲- 美国人，并导致不规则的子宫出血和贫血，需要超过20万子宫切除术 每年在美国。我们的长期目标是了解新的临床相关和医学靶向 负责子宫LM的发病机制和生长，以减少相关的 发病率我们建议并请求资金支持西北子宫肌瘤研究 中心，包括三个高度协调和协同的研究项目，一个行政核心和一个 教育和推广核心。两个相互排斥的关键驱动体细胞突变（mut-）或重排 (-ra)影响MED 12和HMGA 2基因已被发现在85%的所有LM，但潜在的 导致肿瘤发生和肿瘤生长的机制仍然未知。我们建议确定 mut-MED 12和HMGA 2-ra对LM细胞的表观基因组编程，LM干细胞（LSC）功能， 这些肿瘤中异源细胞群的发展，以及全基因组孕酮（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， 确定基因型特异性治疗靶点，用于开发LM的精确医学治疗。项目1 （布伦/尹/戴）将测试mut-MED 12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的组蛋白修饰，从而增强LM中的P4作用 中间细胞群（LIC），其为LSC存活和增殖提供支持生态位。计划2 （Rajkovic）将检验影响MED 12和HMGA 2的不同驱动突变决定细胞凋亡的假设。 和分子异质性。通过细胞命运追踪研究，我们将确定 mut-MED 12细胞是否在子宫肌层中产生不同的细胞群，这些细胞群驱动子宫肌层的形成， LM。项目3（Chakravarti/Wei）将检验LM中HMGA 2过表达改变3D的假设。 染色质相互作用和表观基因组来改变发育、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LM细胞群和人- 子宫组织中具有mut-MED 12的LM的等效小鼠模型。教育和外联核心将 通过发展沟通，推广， 和教育战略，以促进健康公平和消除劳动市场的差距，让公众参与， 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，并将协同个别研究项目的工作， 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的发展。 LM的特征选择性治疗方法，将该领域推向个性化医疗领域。

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.