Roles of DNA methylation in gastrointestinal smooth muscle cells

DNA甲基化在胃肠道平滑肌细胞中的作用

• 批准号: 8893074
• 负责人: Seungil Ro
• 金额: $ 30.92万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8893074
• 关键词: Address; Affect; Animal Model; Animals; Attention; Behavior; Binding; Binding Sites; Boxing; Cell Differentiation process; Cells; Complex; CpG Islands; DNA; DNA Methylation; Development; Diagnostic; Disease; Embryo; Enteric Nervous System; Epigenetic Process; Feedback; Functional disorder; Gastrointestinal Motility; Gastrointestinal tract structure; Gene Expression; Gene Expression Profile; Genes; Genetic; Human; Hypertrophy; Knockout Mice; Knowledge; Link; Maps; Messenger RNA; MicroRNAs; Molecular; Motor; Mus; Muscle Contraction; Muscle relaxation phase; Mutation; Neuromuscular Diseases; Patients; Phenotype; Principal Investigator; Promoter Regions; Reporting; Role; Serum; Serum Response Factor; Site; Smooth Muscle; Smooth Muscle Myocytes; Testing; Transgenic Animals; Work; cell growth; cell motility; cell type; gastrointestinal; interstitial; interstitial cell; motility disorder; mouse model; programs; promoter; therapeutic target; tool

DESCRIPTION (provided by applicant): Gastrointestinal (GI) neuromuscular disorders (motility disorders) are characterized by dysfunctions of three types of key cells: interstitial cels of Cajal (ICC), enteric nervous system (ENS), and smooth muscle cells (SMCs), which cooperatively control SM motility in the GI tract. ENS and ICC generate complex rhythmic motor behavior and spontaneous electrical slow waves, respectively, both of which control SMCs, the final effectors for muscle contraction and muscle relaxation. Although there has been a significant amount of work investigating the effects of ENS and ICC dysfunction in GI motility disorders, the dysfunction of SMCs has received much less attention. The gap in the knowledge of SMC dysfunction needs to be addressed, since the three types of cells are physically associated and functionally working together: dysfunction of one cell type can affect the other two. This present project seeks to uncover a molecular mechanism for understanding how SMCs are remodeled during the development of GI motility disorders. We have recently reported that GI SMCs require microRNAs (miRNAs) for the development and survival of animals, and that the phenotypes of GI SMCs are controlled by serum response factor (SRF)-dependent microRNAs. In addition, our preliminary study suggested that the phenotypic change (hypertrophy) of SMCs is linked to dysregulation of a unique set of SRF-dependent miRNAs which are regulated by epigenetic DNA methylation. To study this new molecular mechanism, we generated six transgenic animal models that display abnormal phenotypes of SMCs during the embryonic and post-natal development of the cells. In this project, we propose three specific aims: define the roles of SRF-dependent miRNAs during the development of GI SMCs, define the roles of DNA methylation during the development of GI SMCs, and discover the roles of DNA methyltransfertase (Dnmt1)-targeting miRNAs that regulate GI SMC hypertrophy. Completion of the specific aims of this project will provide an exciting new mechanism for understanding how the SRF-dependent miRNA genes are epigenetically reprogrammed in the SMCs of GI neuromuscular disorders. Identifying the epigenetic changes will aid not only in the development of a diagnostic tool for hypertrophy-related diseases, but also of a therapeutic target that has the potential to reverse the epigenetic changes that are responsible for these pathological conditions, and thus possibly reverse some of the unwanted pathological changes that occur in these disorders.

描述（由申请人提供）：胃肠道（GI）神经肌肉疾病（运动障碍）的特征是三种关键细胞的功能障碍：卡哈尔间质细胞（ICC）、肠神经系统（ENS）和平滑肌细胞（SMC），它们协同控制胃肠道中的 SM 运动。 ENS 和 ICC 分别产生复杂的节律性运动行为和自发电慢波，两者都控制 SMC，即肌肉收缩和肌肉松弛的最终效应器。尽管已经有大量工作研究 ENS 和 ICC 功能障碍对胃肠道运动障碍的影响，但 SMC 功能障碍受到的关注要少得多。需要解决 SMC 功能障碍知识方面的差距，因为这三种类型的细胞在物理上相关且在功能上协同工作：一种细胞类型的功能障碍可能会影响其他两种细胞类型。本项目旨在揭示一种分子机制，以了解 SMC 在胃肠道运动障碍的发展过程中如何重塑。我们最近报道，胃肠道平滑肌细胞需要微小RNA（miRNA）来维持动物的发育和生存，并且胃肠道平滑肌细胞的表型由血清反应因子（SRF）依赖的微小RNA控制。此外，我们的初步研究表明，SMC 的表型变化（肥大）与一组独特的 SRF 依赖性 miRNA 的失调有关，这些 miRNA 受表观遗传 DNA 甲基化的调节。为了研究这种新的分子机制，我们建立了六种转基因动物模型，这些模型在细胞的胚胎和产后发育过程中表现出异常的 SMC 表型。在这个项目中，我们提出了三个具体目标：定义SRF依赖性miRNA在GI SMC发育过程中的作用，定义DNA甲基化在GI SMC发育过程中的作用，以及发现DNA甲基转移酶（Dnmt1）靶向miRNA在调节GI SMC肥大中的作用。该项目具体目标的完成将为了解 SRF 依赖性 miRNA 基因如何在胃肠道神经肌肉疾病的 SMC 中进行表观遗传重编程提供令人兴奋的新机制。识别表观遗传变化不仅有助于开发肥大相关疾病的诊断工具，而且有助于开发有可能逆转导致这些病理状况的表观遗传变化的治疗靶点，从而可能逆转这些疾病中发生的一些不需要的病理变化。