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：
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
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/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

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.

迄今为止，我们还不明白为什么绝经前子宫肌瘤的患病率如此之高我们也不了解这种疾病中观察到的种族差异的原因。黑人女性往往到组。属于角色脱氧核糖核酸假设添加，体内平衡的和分析细胞将要比其他种族更早出现肿瘤，数量更多，尺寸更大，症状更严重我们研究了平滑肌瘤肿瘤生长和存活的分子机制，因为它对激素和信号通路的影响，发现活性氧 (ROS) 发挥着重要作用在平滑肌瘤发病机制中。此外，我们首次发现 ROS 水平及其对与白人女性相比，黑人女性的子宫肌层和平滑肌瘤组织有所增加。我们认为ROS促进MED12基因突变，促进平滑肌瘤肿瘤形成。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环境以保护肿瘤免受高ROS水平的毒性。我们建议机械分子分析来检验我们的假设，包括长期使用 ROS 治疗时的突变分析， ER 和 PR 在染色质上的占据对 ROS 的响应，我们测试了 BCL2 抑制剂的靶点当雌激素和孕激素缺失时，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，这将产生有价值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并提供使用 BCL2 抑制剂治疗平滑肌瘤的生物学原理。