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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

基本信息

批准号：
10410463
负责人：
Ji-Yong Julie Kim
金额：
$ 15.35万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
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/10410463
关键词：
Acetates 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 Europe Event Exons Fibroid Tumor GNRH1 gene Genes Genomic DNA Genomic Instability Gonadal Steroid Hormones Growth High Prevalence Homeostasis Hormones Hysterectomy Incidence Infertility Knowledge Lead Learning Leiomyoma Medical Medical Care Costs Mitochondria Molecular Molecular Analysis Morbidity - disease rate Mutation Mutation Analysis Myometrial Nucleotides OGG1 gene Oxidative Stress Oxides 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 Steroidal Estrogen Stress Superoxide Dismutase Symptoms Testing Time Tissues Toxic effect United States Uterine Fibroids Woman analog black women deep sequencing disabling symptom high risk population hormonal signals inhibitor insight mitochondrial metabolism myometrium novel racial difference racial disparity receptor repair enzyme reproductive response senescence side effect survival disparity translational applications treatment strategy tumor tumor growth tumor initiation

项目摘要

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.

到目前为止，我们还不明白为什么绝经前子宫肌瘤的发病率如此之高。我们也不了解在这种疾病中观察到种族差异的原因。黑人女性倾向于至组。涉及到角色脱氧核糖核酸假设此外，动态平衡和分析单元格将要与其他种族相比，肿瘤发生得更早，数量更多，体积更大，症状更多我们已经研究了与子宫肌瘤生长和生存有关的分子机制对激素和信号转导途径的研究发现，活性氧(ROS)起着显著的作用在肌瘤发病机制中的作用。此外，我们第一次发现，ROS水平和对与白人妇女相比，黑人妇女子宫肌层和子宫肌瘤组织中的蛋白增加。我们 ROS促进MED12基因的突变，从而促进肌瘤的形成。在……里面 ROS促进子宫肌瘤的生长和存活，因为雌激素和孕激素提供了保护肿瘤免受高ROS水平的毒性的环境。我们提出机械论分子分析来验证我们的假设，包括对ROS慢性治疗的突变分析， ER和PR在染色质上的占有率对ROS的响应，我们测试了BCL2抑制剂的靶向性当缺乏雌激素和黄体酮时，ROS会促进衰老。在我们所有的研究中，我们比较黑人和白人女性的组织将产生有价值的和新的洞察力在肌瘤中观察到的种族差异。我们将学习可能导致子宫肌瘤的早期变化并为bcl2抑制剂治疗子宫肌瘤提供生物学基础。