Probing Mediator 12 function in uterine fibroids

探索Mediator 12在子宫肌瘤中的功能

• 批准号: 9130607
• 负责人: DEBABRATA CHAKRAVARTI
• 金额: $ 18.84万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-20 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9130607
• 关键词: Address; Affect; Amino Acids; Apoptosis; Aspartate; Automobile Driving; Benign; Binding; Bioinformatics; Biological Assay; Biology; Cell Proliferation; Cells; Communication; Complex; DNA Polymerase II; Data Set; Defect; Deposition; Development; Disease; Estrogens; Event; Extracellular Matrix; Fibroid Tumor; Fibrosis; Formulation; Frequencies; Future; Gene Expression; Genes; Glycine; Goals; Growth; Health; Human; Laboratories; Leiomyoma; Link; Mediator of activation protein; Molecular; Mutation; Myometrial; Nuclear Receptors; Ovarian Steroid Hormone; Patients; Play; Progesterone; Proteins; RNA; RNA Polymerase II; Recruitment Activity; Research; Research Proposals; Role; Sampling; Signal Transduction; Smad Proteins; Smad protein; Smooth Muscle; Smooth Muscle Tumor; Testing; Therapeutic; Time; Transcriptional Regulation; Transforming Growth Factor beta; Uterine Fibroids; Woman; Work; actionable mutation; base; clinically significant; cofactor; deep sequencing; genome-wide; human disease; innovation; mutant; next generation; novel; public health relevance; receptor; therapeutic target; transcription factor

 DESCRIPTION (provided by applicant): Uterine leiomyomas, also known as uterine fibroids, are benign, fibrotic smooth muscle tumors that affect an alarming 75-80% of women in their lifetime and constitute a major health problem worldwide. They remain shockingly understudied with few nonsurgical therapeutic options. In a major breakthrough in the field, mutations in the transcriptional mediator complex subunit 12, termed Med 12, have been identified at very high frequency in leiomyoma implying that Med12 mutations are the driver mutations. However, how Med12 and its mutations contribute to leiomyoma is completely unknown. The long term goal of our laboratory is to discover novel molecular events driving leiomyoma. The immediate goal of this R21-exploratory application is to test the hypothesis that Med12 mutations function by generating an altered Med12/mediator cistrome in leiomyoma, leading to abnormal expression of cell proliferation/apoptosis and profibrotic genes. We will determine the genome wide binding profile of wild type and mutant Med12 and other key mediator subunits in normal myometrial and leiomyoma primary cells. Using bioinformatic and ChIP qPCR analysis we will determine whether Med12 functions primarily by targeting communication between transcription factors such as nuclear receptors and Smad proteins, mediator complex and RNA polymerase II and establish that such interactions are defective/altered in leiomyoma. Together, these results will determine for the first time molecular defects in Med12 in leiomyoma thereby advancing the field in an unprecedented manner. Additionally, the proposed exploratory analyses will generate new hypothesis for future RO1-type research proposals in this highly understudied human health problem. The proposed work is scientifically, translationally, and clinically significant because i will provide a new perspective on the key driver mechanisms of Med 12 function in leiomyoma development and open up possibilities for identifying additional therapeutic targets and strategies to treat this disease. It is innovative because it represents the first systematic exploration of previously unrealized roles of Med12 in leiomyoma patho-biology.

 描述（由申请人提供）：子宫平滑肌瘤，也称为子宫肌瘤，是一种良性的纤维化平滑肌肿瘤，影响了75-80%的妇女在其一生中，并构成了一个主要的健康问题世界各地。他们仍然令人震惊地研究不足，几乎没有非手术治疗的选择。在该领域的一项重大突破中，已在平滑肌瘤中以非常高的频率鉴定了转录介质复合物亚基12（称为Med 12）的突变，这意味着Med 12突变是驱动突变。然而，Med 12及其突变如何促进平滑肌瘤是完全未知的。我们实验室的长期目标是发现新的分子事件驱动平滑肌瘤。该R21探索性应用的直接目标是检验Med 12突变通过在平滑肌瘤中产生改变的Med 12/介体顺式组而起作用，从而导致细胞增殖/凋亡和促纤维化基因的异常表达的假设。我们将确定野生型和突变型Med 12和其他关键介质亚基在正常子宫肌层和平滑肌瘤原代细胞的全基因组结合谱。使用生物信息学和ChIP qPCR分析，我们将确定Med 12是否主要通过靶向转录因子如核受体和Smad蛋白，介体复合物和RNA聚合酶II之间的通信发挥作用，并确定这种相互作用在平滑肌瘤中是有缺陷的/改变的。总之，这些结果将首次确定子宫肌瘤中Med 12的分子缺陷，从而以前所未有的方式推进该领域。此外，拟议的探索性分析将产生新的假设，为未来的RO 1型研究建议，在这个高度不足的人类健康问题。拟议的工作在科学上，预防上和临床上都具有重要意义，因为我将为Med 12在平滑肌瘤发展中的关键驱动机制提供新的视角，并为确定治疗这种疾病的其他治疗靶点和策略开辟可能性。它具有创新性，因为它代表了对Med 12在子宫肌瘤病理生物学中以前未实现的作用的首次系统探索。