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.

子宫平滑肌瘤（LM，肌瘤）是女性中最常见的肿瘤，尤其影响非洲裔