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: 8277144
• 负责人: Seungil Ro
• 金额: $ 31.79万
• 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 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8277144
• 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. PUBLIC HEALTH RELEVANCE: Dysfunction of smooth muscle cells (SMCs) is linked to gastrointestinal (GI) neuromuscular disorders, but the molecular mechanism of GI SMC dysfunction is unknown. This study seeks to uncover how SMCs are genetically remodeled during the development of GI neuromuscular disorders.

描述（由申请人提供）：胃肠（GI）神经肌肉疾病（运动性疾病）的特征在于三种类型的关键细胞功能障碍：Cajal间质性神经元（ICC）、肠神经系统（ENS）和平滑肌细胞（SMC），它们共同控制胃肠道中的SM运动性。ENS和ICC分别产生复杂的节律性运动行为和自发电慢波，它们都控制SMC，SMC是肌肉收缩和肌肉松弛的最终效应器。虽然已经有大量的工作调查ENS和ICC功能障碍在GI动力障碍中的作用，但SMCs的功能障碍受到的关注要少得多。SMC功能障碍知识的差距需要解决，因为这三种类型的细胞在物理上是相关的，并在功能上一起工作：一种细胞类型的功能障碍可以影响其他两种。本项目旨在揭示一个分子机制，了解如何平滑肌细胞在胃肠道动力障碍的发展过程中重塑。我们最近报道胃肠道SMC需要microRNA（miRNA）来维持动物的发育和生存，并且胃肠道SMC的表型受到血清反应因子（SRF）依赖性microRNA的控制。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miRNAs的失调有关，这些miRNAs受表观遗传DNA甲基化的调节。为了研究这一新的分子机制，我们建立了6个转基因动物模型，这些模型在胚胎和出生后细胞发育过程中显示出SMC的异常表型。在这个项目中，我们提出了三个具体的目标：定义在胃肠道平滑肌细胞的发展过程中的SRF依赖的miRNA的作用，定义在胃肠道平滑肌细胞的发展过程中的DNA甲基化的作用，并发现DNA甲基转移酶（Dnmt 1）靶向的调控胃肠道平滑肌细胞肥大的miRNA的作用。该项目具体目标的完成将为理解SRF依赖性miRNA基因如何在GI神经肌肉疾病的SMC中表观遗传学重编程提供令人兴奋的新机制。鉴定表观遗传变化将不仅有助于开发肥大相关疾病的诊断工具，而且有助于开发具有逆转导致这些病理状况的表观遗传变化的潜力的治疗靶点，从而可能逆转这些疾病中发生的一些不需要的病理变化。 公共卫生关系：平滑肌细胞（SMC）功能障碍与胃肠道（GI）神经肌肉疾病有关，但GI SMC功能障碍的分子机制尚不清楚。这项研究旨在揭示如何SMCs的基因改造过程中的GI神经肌肉疾病的发展。