Co-regulatory Model of Smooth Muscle Myogenesis

平滑肌肌生成的协同调节模型

• 批准号: 6883971
• 负责人: KIRK M. MCHUGH
• 金额: $ 27.64万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6883971
• 关键词: actins; antisense nucleic acid; cell differentiation; cytogenetics; fluoresceins; gastrointestinal system; genetic library; genetic regulation; genetically modified animals; laboratory mouse; laboratory rat; muscle cells; myoblasts; myogenesis; phenotype; smooth muscle; tissue /cell culture; transcription factor

DESCRIPTION (provided by applicant): Smooth muscle is critical to the normal development and function of the gastrointestinal (GI) tract, while the dysregulation of smooth muscle differentiation results in GI pathologies ranging from birth defects to inflammatory diseases to smooth muscle tumors. A key component in either the development or progression of each of these diseases is an alteration in GI smooth muscle cell (SMC) phenotype. These phenotypic changes consistently reflect a shift from the mature smooth muscle myocyte towards the less differentiated smooth muscle myoblast. The fact that similar changes in SMC phenotype are observed independent of disease etiology suggests that these pathologies converge upon a common cellular pathway that controls or maintains GISMC differentiation. The long-term objectives of this proposal are to gain a better understanding of the critical events modulating GISMC differentiation in both normal and pathogenic GISMCs. Recent studies in our lab indicate that GI smooth muscle differentiation requires the coordinate activation of a distinct subset of transcription factors including serum response factor (SRF), Nkx2-3, and an unidentified AT-rich binding factor. Activity of this regulatory complex centers upon SRF binding to a core CArG-box domain, and appears both developmental and tissue-specific. In addition, our studies indicate that altered patterns of transcription factor utilization are associated with smooth muscle pathogenesis. Clarifying the key role that SRF plays in modulating smooth muscle differentiation is therefore critical to gaining a better understanding of GI smooth muscle development and pathogenesis. To this end, we plan to functionally assess the role of SRF in modulating GI smooth muscle differentiation using morpholino-based antisense technology and transgenic mice. In addition, we will identify and characterize a unique, smooth muscle myoblast-specific AT-rich binding factor found associated with the SRF-Nkx2-3 transcriptional complex in an effort to determine its role in regulating gene expression in this important cellular phenotype.

描述（由申请人提供）：平滑肌对于胃肠道（GI）的正常发育和功能至关重要，而平滑肌分化的失调会导致胃肠道病理，包括出生缺陷、炎症性疾病和平滑肌肿瘤。这些疾病发生或进展的一个关键因素是胃肠道平滑肌细胞 (SMC) 表型的改变。这些表型变化一致反映了从成熟平滑肌肌细胞向分化程度较低的平滑肌成肌细胞的转变。观察到的 SMC 表型的类似变化与疾病病因无关，这一事实表明这些病理学集中在控制或维持 GISMC 分化的共同细胞途径上。该提案的长期目标是更好地了解正常和致病 GISMC 中调节 GISMC 分化的关键事件。我们实验室最近的研究表明，胃肠道平滑肌分化需要协调激活一组不同的转录因子，包括血清反应因子 (SRF)、Nkx2-3 和一种未知的富含 AT 的结合因子。该调节复合物的活性集中于 SRF 与核心 CArG-box 结构域的结合，并且具有发育和组织特异性。此外，我们的研究表明转录因子利用模式的改变与平滑肌发病机制有关。因此，阐明 SRF 在调节平滑肌分化中所起的关键作用对于更好地了解胃肠道平滑肌发育和发病机制至关重要。为此，我们计划使用基于吗啉代的反义技术和转基因小鼠来功能性评估SRF在调节胃肠道平滑肌分化中的作用。此外，我们将鉴定和表征与 SRF-Nkx2-3 转录复合物相关的独特的平滑肌成肌细胞特异性富含 AT 的结合因子，以确定其在调节这一重要细胞表型中的基因表达中的作用。