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：
10330261
负责人：
Ayman Al-Hendy
金额：
$ 8.82万
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/10330261
关键词：
Accounting Address Affect Africa Africa South of the Sahara African African American Animal Model Apoptosis BRCA1 gene Benign Biochemical Caucasians Cell Proliferation Cell model Chicago Cholecalciferol Chromosomal Loss Chromosomal Rearrangement Collaborations Complement Consent DNA Damage DNA Double Strand Break DNA Repair Pathway Development Down-Regulation Epigallocatechin Gallate Ethnic Origin Etiology Experimental Designs Female Genital Neoplasms Fertility Fibroid Tumor Fibrous capsule of kidney Freezing Funding Future Gene Expression Gene Expression Profiling Genes Genetic Genetic Transcription Genomic Instability Ghana Goals Health Health Care Costs Hospitals Human Hysterectomy Impairment In Vitro Incidence Inflammation Infrastructure Intervention Kenya Leiomyoma Lesion Link Mediator of activation protein Medical Medical center Modeling Molecular Morbidity - disease rate National Institute of Child Health and Human Development Natural Products Operative Surgical Procedures Oral Pathogenesis Pathway interactions Patients Perioperative Premenopause Procedures Process Protocols documentation Publishing Race Receptor Signaling Relative Risks Reporting Research Research Priority Risk Sampling Savings Serum Ships Signal Pathway Signal Transduction Somatic Mutation Supplementation Therapeutic Therapeutic Embolization Therapeutic Intervention Time Tissues Training Treatment Efficacy Tumor Burden Universities Uterine Fibroids Uterine myomectomy Vitamin D Vitamin D Deficiency Vitamin D3 Receptor Vitamin Deficiency Woman Women&apos s Health base black women cost effective cost estimate design driving force fertility preservation gene repair health disparity healthy pregnancy human model innovation mortality mouse model mutant myometrium neoplastic novel parent grant pre-clinical racial disparity response stem cells transcriptome sequencing transcriptomics tumor tumor growth tumor progression

Accounting Address Affect Africa Africa South of the Sahara African African American Animal Model Apoptosis BRCA1 gene Benign Biochemical Caucasians Cell Proliferation Cell model Chicago Cholecalciferol Chromosomal Loss Chromosomal Rearrangement Collaborations Complement Consent DNA Damage DNA Double Strand Break DNA Repair Pathway Development Down-Regulation Epigallocatechin Gallate Ethnic Origin Etiology Experimental Designs Female Genital Neoplasms Fertility Fibroid Tumor Fibrous capsule of kidney Freezing Funding Future Gene Expression Gene Expression Profiling Genes Genetic Genetic Transcription Genomic Instability Ghana Goals Health Health Care Costs Hospitals Human Hysterectomy Impairment In Vitro Incidence Inflammation Infrastructure Intervention Kenya Leiomyoma Lesion Link Mediator of activation protein Medical Medical center Modeling Molecular Morbidity - disease rate National Institute of Child Health and Human Development Natural Products Operative Surgical Procedures Oral Pathogenesis Pathway interactions Patients Perioperative Premenopause Procedures Process Protocols documentation Publishing Race Receptor Signaling Relative Risks Reporting Research Research Priority Risk Sampling Savings Serum Ships Signal Pathway Signal Transduction Somatic Mutation Supplementation Therapeutic Therapeutic Embolization Therapeutic Intervention Time Tissues Training Treatment Efficacy Tumor Burden Universities Uterine Fibroids Uterine myomectomy Vitamin D Vitamin D Deficiency Vitamin D3 Receptor Vitamin Deficiency Woman Women&apos s Health base black women cost effective cost estimate design driving force fertility preservation gene repair health disparity healthy pregnancy human model innovation mortality mouse model mutant myometrium neoplastic novel parent grant pre-clinical racial disparity response stem cells transcriptome sequencing transcriptomics tumor tumor growth tumor progression

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项目摘要

Abstract of Funded Parent Grant UFs (leiomyomas) are the most important benign neoplastic threat to women’s health worldwide, with annual health care costs estimated in the hundreds of billions of dollars. UF caused- morbidities negatively impact women of all ethnicities, but disproportionately affect African American (AA) women, who have a threefold higher incidence rate and relative risk of UFs than Caucasian (CC) women. While the basis for this risk disparity is not fully understood, recent studies implicate hypovitaminosis D as a major contributor. Thus, AA women have a tenfold increased risk of vitamin D deficiency compared to CC women, and as we first reported, UF risk is inversely correlated with 25-hydroxy vitamin D serum levels. Nonetheless, it is not clear whether and how the processes that drive UF formation and racial risk disparity are genetically or biochemically linked. Herein, we suggest a mechanistic basis to couple UF etiology and relative risk association through a functional interplay between vitamin D3 and an altered DNA damage response network in MED12-mutant UFs, and further offer proof of concept for therapeutic intervention in this genetic setting. Recently, we and others identified somatic mutations in the transcriptional Mediator subunit MED12 as the dominant drivers of UFs, accounting for ~70% of tumors. Notably, MED12-mutant UFs are characterized by significant chromosomal loss and rearrangement, suggesting genomic instability as a driving force in tumor progression. Herein, we clarify the molecular basis for mutant MED12-driven genomic instability, and further identify vitamin D3 receptor signaling as a likely suppressor of this process. We show that MED12-mutant UF stem cells (SCs) accumulate high levels of unrepaired DNA double-strand breaks (DSBs) through downregulation of key DNA damage response (DDR) and repair genes, including RAD50, RAD51 and BRCA1. Notably, we find the vitamin D3/receptor axis to be a variable modulator of MED12-regulated DDR gene expression. Thus, we show that reduced vitamin D3/receptor signaling suppresses, while elevated signaling activates, DDR genes downregulated in MED12-mutant UF SCs. Based on these findings, we hypothesize that hypovitaminosis D exacerbates DNA damage accumulation and genomic instability arising in MED12-mutant UFs, leading to enhanced tumor progression and burden. Accordingly, we propose that vitamin D3, through reparation of an impaired DDR, will provide therapeutic benefit in MED12-mutant tumors. To confirm and extend these hypotheses, we propose the following aims, which directly address and mechanistically connect three overarching issues in the field: the molecular pathogenesis of UFs, the racial disparity in UF risk, and the development of novel tolerable fertility-saving and cost-effective oral therapies for UFs.

资助的父母赠款摘要 UFS（平滑肌瘤）是对全球妇女健康的最重要的肿瘤威胁，每年的医疗保健费用估计为数千亿美元。 UF引起的 - 病态对所有种族的妇女产生负面影响，但对非洲的影响不成比例美国（AA）妇女，其事件率高三倍，UF的相对风险比高加索人（CC）妇女。虽然这种风险差异的基础尚未完全理解，但最近研究暗示了次生胺病D是主要贡献者。那是妇女有十倍与CC妇女相比，维生素D缺乏症的风险增加，并且正如我们首次报道的那样，UF风险与25-羟基维生素D血清水平成反比。但是，尚不清楚是否以及驱动UF形成和种族风险差异的过程通常是一般或生化链接。在此，我们建议将uf病因和相对的机械基础通过维生素D3与DNA损伤改变的功能相互作用的风险关联 Med12突变UFS中的响应网络，并进一步提供治疗概念证明在这种遗传环境中进行干预。最近，我们和其他人在转录中介子亚基Med12作为UFS的主要驱动因素，约为70％值得注意的是，Med12突变剂的UF的特征是明显的染色体损失和重排，表明基因组不稳定性是肿瘤进展中的驱动力。这里，我们阐明突变Med12驱动的基因组不稳定性的分子基础，并进一步识别维生素D3受体信号传导可能是该过程的抑制剂。我们证明了Med12突出剂 UF干细胞（SC）积累了高水平的未修复的DNA双链断裂（DSB）通过下调关键DNA损伤响应（DDR）和修复基因，包括Rad50， RAD51和BRCA1。值得注意的是，我们发现维生素D3/受体轴是可变的调节剂 Med12调节的DDR基因表达。那我们表明维生素D3/受体减少了信号抑制，同时发出升高的信号传导激活的DDR基因在Med12突变的UF SC中下调。基于这些发现，我们假设降压毒素病D加剧了DNA损伤积累和基因组在Med12突变的UF中产生的不稳定性，导致肿瘤进展增强和伯宁。根据，我们建议通过受损的DDR反应维生素D3提供 Med12突变肿瘤的治疗益处。为了确认并扩展这些假设，我们提案以下目的，直接解决并机械连接三个现场的总体问题：UF的分子发病机理，UF的种族差异风险，以及新型可忍受的养育和具有成本效益的口服疗法的发展 UFS。