Co-regulatory Model of Smooth Muscle Myogenesis

描述(申请人提供)：平滑肌对胃肠道(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从出生缺陷到炎症性疾病到平滑肌肿瘤的一系列GI病理。胃肠道平滑肌细胞(SMC)表型的改变是这些疾病发生或发展的关键因素。这些表型变化一致地反映了从成熟的平滑肌肌细胞向分化较少的肌成肌细胞的转变。事实上，SMC表型的相似变化独立于疾病病因而观察到，这表明这些病理学聚集在控制或维持GISMC分化的共同细胞途径上。这一建议的长期目标是更好地了解在正常和致病的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一组不同的转录因子的协同激活，包括血清反应因子(SRF)、Nkx2-3和一个未知的富含AT的结合因子。这种调节复合体的活性集中在SRF与核心Carg-box结构域的结合上，并表现出发育和组织特异性。此外，我们的研究表明，转录因子利用模式的改变与平滑肌的发病机制有关。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的发育和发病机制是至关重要的。为此，我们计划利用基于吗啡的反义技术和转基因小鼠，从功能上评估SRF在调节胃肠道平滑肌分化中的作用。此外，我们将鉴定和鉴定与SRF-Nkx2-3转录复合体相关的独特的、平滑肌成肌细胞特异的AT丰富的结合因子，以努力确定它在调节这一重要细胞表型的基因表达中的作用。

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.