Reactive Oxygen Species in the Initiation, Survival and Racial Disparity of Uterine Leiomyoma

活性氧在子宫平滑肌瘤的发生、存活和种族差异中的作用

• 批准号: 10655328
• 负责人: Ji-Yong Julie Kim
• 金额: $ 45.96万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-06 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655328
• 关键词: Acetates; Acetylation; Acute; Address; Affect; Age; Area; BCL2 gene; Biological; Black race; Cell Death; Cell Survival; Cells; Cessation of life; Chromatin; Chronic; DNA; DNA Sequence Alteration; Data; Development; Disease; Drug Metabolic Detoxication; Environment; Enzymes; Estrogens; Ethnic Origin; Europe; Event; Exons; Fibroid Tumor; GNRH1 gene; Genes; Genomic DNA; Genomic Instability; Gonadal Steroid Hormones; Growth; High Prevalence; Homeostasis; Hormones; Hysterectomy; Incidence; Infertility; Knowledge; Knowledge acquisition; Learning; Leiomyoma; Medical; Medical Care Costs; Mitochondria; Molecular; Molecular Analysis; Morbidity - disease rate; Mutation; Mutation Analysis; Myometrial; Nucleotides; OGG1 gene; Oxidative Stress; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Play; Premenopause; Prevention strategy; Production; Progesterone; Progesterone Receptors; Protein Family; Public Health; Publishing; Race; Reactive Oxygen Species; Regulation; Role; SOD2 gene; Seminal; Signal Pathway; Stress; Superoxide Dismutase; Symptoms; Testing; Time; Tissues; Toxic effect; United States; Uterine Fibroids; Woman; analog; black women; deep sequencing; disabling symptom; high risk population; inhibitor; insight; mitochondrial metabolism; myometrium; novel; racial difference; racial disparity; racial population; receptor; repair enzyme; reproductive; response; senescence; side effect; survival disparity; translational applications; treatment strategy; tumor; tumor growth; tumor initiation

To date, we do not understand why there is such a high prevalence of uterine leiomyoma in premenopausal women nor do we understand the reasons for the racial disparity observed in this disease. Black women tend to groups. pertains role DNA hypothesize addition, homeostatic and analysis cells will develop tumors earlier and are more numerous, larger in size and more symptomatic than other ethnic We have studied the molecular mechanisms involved in leiomyoma tumor growth and survival as it to hormones and signaling pathways and found that reactive oxygen species (ROS) plays a significant in leiomyoma pathogenesis. Moreover, for the first time, we discovered that ROS levels and effects on are increased in the myometrial and leiomyoma tissues of Black compared to White women. We that ROS promotes mutations in the MED12 gene, to promote leiomyoma tumor formation. In ROS promotes growth and survival of the leiomyoma tumors as estrogen and progesterone provide a environment to protect the tumors from the toxicity of high ROS levels. We propose mechanistic molecular analyses to test our hypothesis including mutational analysis upon chronic treatment with ROS, of ER and PR occupancy on chromatin in response to ROS, and we test the BCL2 inhibitors to target where ROS promotes senescence when estrogen and progesterone are absent. In all of our studies, we compare the tissues from Black versus white women which willgenerate valuable and novel insight into the racial disparity observed in leiomyoma. We will learn about early changes that may lead to leiomyoma development as well as provide biological rationale to treat leiomyoma tumors with the BCL2 inhibitors.

迄今为止，我们不明白为什么绝经前子宫肌瘤的发病率如此之高 我们也不理解在这种疾病中观察到的种族差异的原因。黑人女性倾向于 到 组 所属 作用 DNA 假设 此外， 自我平衡 和 分析 细胞 将 比其他种族的人更早患上肿瘤，数量更多，体积更大，症状更明显。 我们研究了平滑肌瘤生长和存活的分子机制， 激素和信号通路，并发现活性氧（ROS）起着重要的作用， 在平滑肌瘤发病机制中的作用。此外，我们第一次发现，ROS水平和对 与白色妇女相比，黑人妇女子宫肌层和平滑肌瘤组织中的我们 ROS促进了MED12基因的突变，从而促进了平滑肌瘤的形成。在 ROS促进平滑肌瘤肿瘤的生长和存活，因为雌激素和孕激素提供了一种抑制平滑肌瘤生长的机制。 保护肿瘤免受高ROS水平的毒性。我们建议机械 分子分析以检验我们的假设，包括用ROS慢性治疗后的突变分析， ER和PR在染色质上的占有率对ROS的反应，我们测试了BCL 2抑制剂靶向 当雌激素和孕激素不存在时，ROS促进衰老。在我们所有的研究中，我们 比较黑人和白色妇女的组织，这将产生有价值的和新颖的见解， 在平滑肌瘤中观察到的种族差异。我们将了解可能导致平滑肌瘤的早期变化 开发以及提供生物学原理，以治疗平滑肌瘤肿瘤与BCL 2抑制剂。

项目成果

Uterine Leiomyosarcoma Associated With Leiomyoma With Bizarre Nuclei: Histology and Genomic Analysis of 2 Cases.

• DOI: 10.1097/pgp.0000000000000837
• 发表时间: 2022-11-01
• 期刊: International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists

Myometrial oxidative stress drives MED12 mutations in leiomyoma.

• DOI: 10.1186/s13578-022-00852-0
• 发表时间: 2022-07-22
• 期刊: CELL AND BIOSCIENCE
• 影响因子: 7.5
• 作者: Li, Yinuo;Xu, Xiuhua;Asif, Huma;Feng, Yue;Kohrn, Brendan F.;Kennedy, Scott R.;Kim, J. Julie;Wei, Jian-Jun
• 通讯作者: Wei, Jian-Jun

Leiomyoma with nuclear atypia: Rare diseases that present a common diagnostic problem.

• DOI: 10.1053/j.semdp.2022.01.006
• 发表时间: 2022-05
• 期刊: Seminars in diagnostic pathology
• 影响因子: 2.3