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

• 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
• 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' 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

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。非裔美国妇女的UF患病率高出3 - 4倍， 在年轻时经常需要手术，肌瘤病变的多样性更高，表现更严重 和并发症的几率更高这种种族/民族差异的病因仍然没有完全弄清楚， 然而，最近的研究表明病因是"多因素的"。父R01补助金的范围集中在 了解维生素D缺乏作为UFs生长和进展的主要危险因素之间的联系， 非洲裔美国人比较女性。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（在编写母公司报告时无法获得） R01）已经显示出维生素D缺乏与肠道微生物组改变之间的密切联系。最近新增 报告（在制备母体R01时也不可用）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， 生殖道微生物组的一致变化。微生物群从有益的丁酸盐- 已经描述了在患有各种疾病的患者中产生针对机会性病原体的细菌 包括癌症然而，维生素D缺乏引起的子宫肌瘤微生物组改变的作用， 这种联系在UF发病机制中的潜在作用以前没有研究过。我们假设 维生素D缺乏症不仅可能加剧MED12- 突变的UF（亲本RO 1的重点领域），而且还调节肠道微生物组（管理的重点领域）。 补充剂），这又导致增强的肿瘤进展和生长。更好地描述变化 局部生殖道微生物组组成和功能潜力，以及与维生素D的关系 UF患者的缺乏将促进有效的新的预防和治疗策略的发展 这种重要而常见的疾病。这些最近发表的报告和额外的初步数据 为这项创新的补充研究创造了前所未有的及时机会 提议