REGULATION OF MITF ACTIVITY IN OSTEOCLASTS

小眼畸形（MITF）突变小鼠的严重骨表型表明，由小眼畸形（MITF）基因编码的螺旋-环-螺旋（HLH） zipper转录因子在多核破骨细胞的终末分化中起重要作用。除了提供一个非常有趣的系统来研究哺乳动物系统中发育调节的基因表达外，研究MITF基因可能对人类疾病有直接的影响。特别是，绝经后妇女的骨质疏松症和多发性骨髓瘤患者发生的溶骨性骨破坏和高钙血症是本研究可能具有潜在影响的临床条件的例子。这项资助的长期目标是在分子水平上确定MITF蛋白在正常破骨细胞生物学中的功能。该提案的具体目标是：1。确定MITF是否是Erk-2在破骨细胞2中的靶标。确定MITF是否是ERK-2在破骨细胞中的靶标。2. 确定MITF是否是破骨细胞Jun激酶（JNK）的靶点。这些研究将在三种实验系统中进行：异源细胞系，体外原代破骨细胞样细胞和小鼠转基因模型中的体内实验。

DESCRIPTION The severe bone phenotype in microphtalmia (MITF) mutant mice indicates that the helix-loop-helix (HLH) zipper transcription factor encoded by the microphthalmia (MITF) gene has significant role in terminal differentiation of multi-nucleated osteoclasts. In addition to providing a very interesting system to study developmentally regulated gene expression in a mammalian system, studying the MITF gene may have direct impact on human disease. In particular, osteoporosis in post- menopausal women and the osteolytic bone destruction and hypercalcemia that occurs in patients with multiple myeloma are examples of clinical conditions where this research may have potential impact. The long term goal of this grant are to determine, at the molecular level, the function of the MITF protein in normal osteoclast biology. The specific aims of the proposal are: 1. To determine if MITF is a target of Erk-2 in osteoclasts 2. To determine if MITF is a target of ERK-2 in osteoclasts. 2. To determine if MITF is a target of Jun kinase (JNK) in osteoclasts. These studies will be performed in three experimental systems: heterologous cell lines, primary osteoclast-like cells in vitro and in vivo in mouse transgenic models.