REGULATION OF SMOOTH MUSCLE DIFFERENTIATION

平滑肌细胞对于循环系统的功能是必不可少的， 泌尿生殖系统、呼吸系统和消化系统，但人们对它们知之甚少。 这些收缩细胞的分化是如何被调节的。 我们的长期目标是深入了解 潜在的平滑肌发育。 我们已经确定， 鉴定了两种高度保守的蛋白质，富含半胱氨酸的蛋白质1 CRP1和CRP2，它们是 在平滑肌衍生物中表达。 CRP或多或少地由 仅两个LIM结构域，双锌指结构， 在许多蛋白质中发现，这些蛋白质在细胞分化中起关键作用 在发展过程中。 最近，CRP家族的第三个成员， 在横纹肌中表达的蛋白质已被证明是必不可少的， 体内心肌和骨骼肌细胞的分化。 我们 假设CRP1和CRP2在分化中起关键作用， 血管和内脏的平滑肌。 CRP1和CRP2在平滑肌肌发生中的作用将被探索 使用鼠标作为模型系统。 空间和时间模式 CRP1和CRP2编码基因的表达将在 通过原位杂交在胚胎和成体中获得高分辨率， 免疫细胞化学方法。 缺乏CRP 1或CRP 2表达的小鼠将 通过靶向基因破坏方法产生， 将评估对平滑肌结构和功能的影响。 为了确定CRP 1和CRP 2在细胞内的分子作用， 的亚细胞分布和结合伴侣库， 蛋白质将被建立。 预计这些研究将提供 机械洞察所需的途径产生顺利 肌肉. 平滑肌细胞在表型可塑性方面是不寻常的。在 对生理刺激的反应，平滑肌细胞可以从 a differentiated分化to a proliferative增殖state状态.平滑肌增生 血管系统中的细胞是发展的主要贡献者， 动脉粥样硬化和血管成形术后再狭窄。 了解 平滑肌分化的分子机制是一种 发展合理治疗的必要前提 控制体内平滑肌细胞行为的方法。

Smooth muscle cells are essential for the function of the circulatory, urogenital, respiratory, and digestive systems, yet little is understood about how the differentiation of these contractile cells is regulated. Our long-term goal is to gain insight into the molecular mechanisms underlying smooth muscle development. We have identified and characterized two highly conserved proteins, cysteine-rich protein 1 (CRP1) and cysteine-rich protein 2 (CRP2), that are prominently expressed in smooth muscle derivatives. CRPs are comprised more or less exclusively of two LIM domains, double zinc finger structures that are found in many proteins that play key roles in cell differentiation during development. Recently, a third member of the CRP family that is expressed in striated muscle has been demonstrated to be essential for the differentiation of cardiac and skeletal muscle cells in vivo. We postulate that CRP1 and CRP2 play critical roles in the differentiation of vascular and visceral smooth muscle. The roles of CRP1 and CRP2 in smooth muscle myogenesis will be explored using the mouse as a model system. The spatial and temporal patterns of expression of the genes encoding CRP1 and CRP2 will be defined at high resolution in embryos and adults by in situ hybridization and immunocytochemical methods. Mice that lack CRP1 or CRP2 expression will be generated by targeted gene disruption methods and the phenotypic consequences for smooth muscle structure and function will be evaluated. In order to define the molecular roles of CRP1 and CRP2 within cells, the subcellular distributions and binding partner repertoires of the proteins will be established. These studies are expected to provide mechanistic insight into a pathway required for the generation of smooth muscle. Smooth muscle cells are unusual in their phenotypic plasticity. In response to physiological stimuli, smooth muscle cells can shift from a differentiated to a proliferative state. Hyperplasia of smooth muscle cells in the vasculature is a central contributor to the development of atherosclerosis and to restenosis after angioplasty. Understanding the molecular mechanisms underlying smooth muscle differentiation is an essential prerequisite to the development of rational therapeutic approaches to control the behavior of smooth muscle cells in vivo.