MI--MODULATING OSTEOCLAST GENE EXPRESSION AND FUNCTION

描述（改编自研究者摘要）：严重的骨 小眼畸形（mi）突变小鼠的表型表明， 螺旋-环-螺旋（HLH）-拉链转录因子，由 小眼畸形（Mi）基因在终末 多核破骨细胞的分化。 除了提供 一个非常有趣的系统来研究发育调控的基因表达 在哺乳动物系统中，研究Mi基因可能直接应用于 重大人类疾病。 尤其是绝经后的骨质疏松症 妇女和溶骨性骨质破坏和高钙血症， 多发性骨髓瘤患者是临床病症的实例， 这项研究可能会产生潜在的影响。 关于知识， 转录调节和信号转导以指数方式增加 新的药理学靶点和干预策略 选择性地与导致人类疾病的过程结合成为可能。 Mi基因座的生物学表明，由该基因编码的产物 可能为治疗人类骨病提供这样的机会。 本申请的长期目标是确定，在分子水平上， 水平，Mi蛋白在正常破骨细胞生物学中的功能。 的 这项建议的具体目标是：1。 以鉴定和表征 在确定的靶基因中的顺式元件由Mi蛋白调节， 破骨细胞谱系。 2. 确定Mi的跨需求 作用于破骨细胞，通过结构功能分析， 基因，而且还通过确定破骨细胞特异性合作伙伴Mi行动。 3. 确定Mi产物如何受CSF-1/c-fms负调控 酪氨酸激酶信号通路，并确定是否 这种调节发生在破骨细胞中。 这些研究将在 在三种实验系统中：异源细胞系，原代 体外培养的破骨细胞样细胞，以及转基因小鼠体内培养的破骨细胞样细胞， 基因模型 这些信息将提出具体的战略， 中断破骨细胞中的Mi功能。

DESCRIPTION (Adapted from investigator's Abstract): The severe bone phenotype in microphthalmia (mi) mutant mice indicates that the helix-loop-helix (HLH)-zipper transcription factor encoded by the microphthalmia (Mi) gene has a significant role in the 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 Mi gene may have direct applications to significant human diseases. 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. As the knowledge concerning transcriptional regulation and signal transduction increases at exponential rates, new pharmacological targets and strategies for interfering selectively with processes that contribute to human disease become possible. The biology of the Mi locus suggests that the product encoded by this gene might provide such opportunities for the treatment of human bone disease. The long term goal of this application is to determine, at the molecular level, the function of the Mi protein in normal osteoclast biology. The specific aims of this proposal are: 1. To identify and characterize cis-elements in identified target genes regulated by the Mi protein in the osteoclast cell lineages. 2. To identify the trans-requirements of Mi action in osteoclasts, both through structure function analysis of the Mi gene, but also by identifying osteoclast-specific partners for Mi action. 3. To determine how the Mi product is negatively regulated by CSF-1/c-fms tyrosine kinase signaling pathways in myeloid cell lines and to determine if this regulation occurs in the osteoclast. These studies will be performed in three experimental systems: heterologous cell lines, primary osteoclast-like cells cultured in vitro, and in vivo in mouse transgenic and genetic models. Such information will suggest strategies to specifically interrupt Mi function in the osteoclast.