Co-regulatory Model of Smooth Muscle Myogenesis

描述（由申请人提供）：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导致从出生缺陷到炎性疾病再到平滑肌肿瘤的GI病理。这些疾病中的每一种的发展或进展的关键组分是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较低的平滑肌成肌细胞的转变。观察到SMC表型的类似变化与疾病病因无关的事实表明，这些病理学会聚在控制或维持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正常和致病性GISMCs中调节GISMCs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个独特的转录因子，包括血清反应因子（SRF），Nkx 2 -3，和一个身份不明的AT丰富的结合因子的子集。该调节复合物的活性以SRF结合至核心CArG盒结构域为中心，并且出现发育和组织特异性。此外，我们的研究表明，改变模式的转录因子利用与平滑肌发病机制。因此，阐明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地评估SRF在调节GI平滑肌分化中的作用。此外，我们将确定和表征一个独特的，平滑肌成肌细胞特异性AT丰富的结合因子，发现与SRF-Nkx 2 -3转录复合物，以确定其在调节基因表达在这一重要的细胞表型的作用。

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.