COREGULATORY MODEL OF SMOOTH MUSCLE MYOGENESIS

平滑肌生肌的核心模型

• 批准号: 6381539
• 负责人: KIRK M. MCHUGH
• 金额: $ 24.32万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 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 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6381539
• 关键词: DNA footprinting; actins; cell differentiation; gastrointestinal disorder; gastrointestinal system; gel mobility shift assay; gene expression; genetic regulatory element; laboratory rat; molecular pathology; myogenesis; newborn animals; nucleic acid sequence; site directed mutagenesis; smooth muscle; tissue /cell culture; transcription factor; transfection; ulcerative colitis

Mature gastrointestinal (GI) smooth muscle cells (SMCs) possess a high degree of developmental plasticity retaining the ability to interconvert between proliferative and differentiated states in response to external stimuli. Dysregulation of GI SMC differentiation is associated with a variety of GI disorders including Hirschsprung's disease, Crohn's disease, ulcerative colitis, motility disorders, and GI smooth muscle tumors. The goal of this proposal is to gain a better understanding of the molecular mechanisms controlling GI smooth muscle development. Our hypothesis is that GI smooth muscle myogenesis is controlled by the synergistic expression of transcription factors that are common to all muscle lineages, as well as those that are smooth muscle specific. This hypothesis is supported by recent data from our lab identifying a key regulatory complex within the gamma-smooth muscle isoactin gene promoter. Interconversion between proliferative and differentiated GI SMC phenotypes involves differential binding of serum response factor (SRF), distinct isotypes of MEF2, and additional unidentified transcription factors to this critical regulatory complex. Utilization of these same transcription factors by this complex is altered in G1 smooth muscle tumors and ulcerative colitis suggesting that SRF and MEF2 may play a role in GI smooth muscle pathogenesis. We plan to identify the key transcription factors involved in GI smooth muscle myogenesis by elucidating the factors controlling gamma-smooth muscle isoactin gene expression in primary cultures of GI SMCs. We will use a unique, mass-arrayed screening technique to isolate and identify novel GI smooth muscle-specific transcription factors. Cultured GI SMCs will be used to assess the functional role that SRF, MEF2, and novel transcription factors play in modulating GI SMC differentiation. Identifying the key transcription factors involved in GI smooth muscle myogenesis, and determining how they interact to modulate GI SMC phenotype is critical to gaining a better understanding of GI smooth muscle pathogenesis in a variety of GI diseases.

成熟的胃肠道（GI）平滑肌细胞（SMC）具有高度的发育可塑性，保留了响应外部刺激而在增殖状态和分化状态之间相互转换的能力。 胃肠道 SMC 分化失调与多种胃肠道疾病相关，包括先天性巨结肠病、克罗恩病、溃疡性结肠炎、运动障碍和胃肠道平滑肌肿瘤。 该提案的目标是更好地了解控制胃肠道平滑肌发育的分子机制。我们的假设是，胃肠道平滑肌肌生成是由所有肌肉谱系共有的转录因子以及平滑肌特异性转录因子的协同表达控制的。 我们实验室的最新数据支持了这一假设，该数据确定了伽马平滑肌异肌动蛋白基因启动子内的关键调控复合物。 增殖型和分化型 GI SMC 表型之间的相互转换涉及血清反应因子 (SRF)、MEF2 的不同同种型以及其他未鉴定的转录因子与这一关键调节复合物的差异结合。该复合物对这些相同转录因子的利用在 G1 平滑肌肿瘤和溃疡性结肠炎中发生改变，表明 SRF 和 MEF2 可能在胃肠道平滑肌发病机制中发挥作用。 我们计划通过阐明控制胃肠道平滑肌异肌动蛋白原代培养物中γ-平滑肌异肌动蛋白基因表达的因素来鉴定参与胃肠道平滑肌肌生成的关键转录因子。 我们将使用独特的质量阵列筛选技术来分离和鉴定新型胃肠道平滑肌特异性转录因子。 培养的 GI SMC 将用于评估 SRF、MEF2 和新型转录因子在调节 GI SMC 分化中的功能作用。鉴定参与胃肠道平滑肌肌生成的关键转录因子，并确定它们如何相互作用以调节胃肠道 SMC 表型，对于更好地了解各种胃肠道疾病中胃肠道平滑肌的发病机制至关重要。