Hypovitaminosis D promotes MED12-associated genomic instability in uterine fibroids

维生素 D 缺乏促进子宫肌瘤中 MED12 相关基因组不稳定性

基本信息

批准号：
9907256
负责人：
Ayman Al-Hendy
金额：
$ 23.7万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-02-15 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9907256
关键词：
Address Administrative Supplement African African American Age Americas Anabolism Anti-inflammatory Antiviral Agents Area Bacteria Benign Butyrates Caucasians Color DNA Damage Data Development Disease Endometrium Enzymes Ethnic Origin Etiology Fibroid Tumor Fibrosis Functional disorder Future Genes Genetic Genomic Instability Grant Growth Gynecologic Gynecology Healthcare Systems High Prevalence Immune Immune response Immunologics Immunosuppression Individual Inflammatory Inflammatory Response Innate Immune Response Interferons Intervention Knockout Mice Knowledge Lead Leiomyoma Lesion Ligands Link Lipid A Lipopolysaccharides Malignant Neoplasms Medical Molecular Mutation Operative Surgical Procedures Other Genetics Parents Pathogenesis Patients Phenotype Play Preparation Prevention Publishing Race Reporting Research Proposals Risk Risk Factors Role Secondary to Serum Signal Transduction TLR4 gene Therapeutic Therapeutic Intervention Time Up-Regulation Uterine Fibroids Uterus Vagina Vitamin D Vitamin D Deficiency Vitamin D3 Receptor Vitamin Deficiency Woman Women&apos s Health base combat comparative cost genital microbiome gut microbiome innovation insight microbial microbiome microbiome alteration microbiome composition microbiota mouse model mutant myometrium neoplastic new therapeutic target novel pathogen racial and ethnic disparities reproductive reproductive tract stem cell niche tool transcriptome sequencing tumor tumor growth tumor progression

项目摘要

Supplement Abstract Race plays an important role in UF risk. African American women have 3–4 times higher prevalence of UFs, frequent need for surgery at younger age, higher multiplicity of fibroids lesions, and more severe manifestations and complications than Caucasian women. The etiology of this racial/ethnic disparity is still not fully understood, however recent studies suggest that etiology is “multi-factorial”. The scope of the parent R01 grant is centered on understanding the link between vitamin D deficiency as a major risk factor for UFs growth and progression in African American compared women. Vitamin D is a well-established anti-inflammatory molecule that influence several components of host immune responses. Recent reports (not available at time of preparation of the parent R01) have shown strong link between vitamin D deficiency, and altered microbiome in the gut. Additional recent reports (also not available at time of preparation of the parent R01) and the preliminary data from our group generate unprecedented and timely opportunity for this innovative supplemental research proposal, have shown consistent variance in reproductive tract microbiome. A general shift in the microbiota from beneficial butyrate- producing bacteria towards opportunistic pathogens has been described in patients with various diseases including cancer. However, the role of vitamin D deficiency-induced alteration uterine fibroids microbiome and the potential role of this link to the pathogenesis of UF has not investigated before. We hypothesize that hypovitaminosis D may not only exacerbates DNA damage accumulation and genomic instability in MED12- mutant UFs (focus area of the parent RO1), but also modulate the gut microbiome (focus area of administrative supplement), which in turn lead to enhanced tumor progression and growth. A better characterization of changes in local reproductive tract microbiome composition and functional potential, and association with vitamin D deficiency in UF patients will facilitate the development of effective novel prevention and therapeutic strategies for this important and common disease. These very recently published reports and additional preliminary data from our group generate unprecedented and timely opportunity for this innovative supplemental research proposal.

补充摘要种族在 UF 风险中起着重要作用，非裔美国女性的 UF 患病率高出 3-4 倍。年龄较小、需要频繁手术、肌瘤病灶复数较多、表现较严重与白人女性相比，这种种族/民族差异的病因仍未完全了解，然而，最近的研究表明，病因是“多因素的”。母公司 R01 资助的范围是集中的。了解维生素 D 缺乏作为 UF 生长和进展的主要危险因素之间的联系与女性相比，非洲裔美国人的维生素 D 是一种公认的抗炎分子。宿主免疫反应的几个组成部分。最近的报告（在家长准备时尚未提供） R01）最近发现维生素 D 缺乏与肠道微生物组改变之间存在密切联系。报告（在准备母版 R01 时也无法获得）和我们小组的初步数据为这项创新的补充研究提案创造了前所未有的及时机会，已经表明生殖道微生物群的一致变化。微生物群从有益的丁酸-普遍转变。已在患有各种疾病的患者中描述了产生针对机会病原体的细菌然而，维生素 D 缺乏引起的子宫肌瘤微生物组改变和癌症的作用。之前尚未研究过这种联系与 UF 发病机制的潜在作用。维生素D缺乏症可能不仅会恶化MED12-中的DNA损伤积累和基因组不稳定性突变体 UF（母体 RO1 的重点区域），还可以调节肠道微生物组（行政管理的重点区域）补充），这反过来又会促进肿瘤的进展和生长，更好地表征变化。局部生殖道微生物组组成和功能潜力以及与维生素 D 的关联 UF患者的缺陷将有助于开发有效的新型预防和治疗策略这些最近发表的报告和其他初步数据。我们小组为这项创新补充研究创造了前所未有的及时机会提议。