Co-regulatory Model of Smooth Muscle Myogenesis

描述（由申请人提供）：平滑肌对胃肠道的正常发育和功能至关重要，而平滑肌分化失调导致从出生缺陷到炎症性疾病到平滑肌肿瘤等胃肠道病理。这些疾病发生或进展的一个关键因素是GI平滑肌细胞（SMC）表型的改变。这些表型变化一致地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。SMC表型的类似变化与疾病病因无关，这一事实表明，这些病理聚集在控制或维持GISMC分化的共同细胞途径上。本提案的长期目标是更好地了解在正常和致病性GISMC中调节GISMC分化的关键事件。我们实验室最近的研究表明，GI平滑肌分化需要一系列转录因子的协同激活，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。这种调控复合物的活性集中在SRF与核心CArG-box结构域的结合上，并且具有发育性和组织特异性。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，明确SRF在调节平滑肌分化中的关键作用对于更好地理解GI平滑肌的发育和发病机制至关重要。为此，我们计划利用基于morpholino的反义技术和转基因小鼠，从功能上评估SRF在调节GI平滑肌分化中的作用。此外，我们将鉴定和表征一种独特的，与SRF-Nkx2-3转录复合物相关的平滑肌成肌细胞特异性AT-rich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。

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.