MI--MODULATING OSTEOCLAST GENE EXPRESSION AND FUNCTION

描述(改编自调查人员摘要)：严重的骨骼 小眼炎(MI)突变小鼠的表型表明 编码的螺旋-环-螺旋(Hlh)-拉链转录因子 小眼球(Mi)基因在终末期有重要作用 多核破骨细胞的分化。除了提供 研究发育调控基因表达的非常有趣的系统 在哺乳动物系统中，研究Mi基因可能直接应用于 重大的人类疾病。尤其是绝经后骨质疏松症 妇女与溶骨性骨破坏和高钙血症 多发性骨髓瘤患者是临床条件的例子 这项研究可能会产生潜在的影响。据了解，关于 转录调控和信号转导呈指数增长 速率、新的药理靶点和干预策略 有选择地利用导致人类疾病的过程成为可能。 Mi基因的生物学特性表明，该基因编码的产物 可能为人类骨病的治疗提供这样的机会。 这项应用的长期目标是在分子水平上确定 水平，Mi蛋白在正常破骨细胞生物学中的功能。这个 这项建议的具体目标是：1.识别和表征 受Mi蛋白调控的已识别靶基因中的顺式元件 破骨细胞系。2.确定小米的反式需求 通过对小鼠结构和功能的分析，对破骨细胞的作用 基因，但也通过识别破骨细胞的特定合作伙伴的米氏作用。 3.确定Mi产物如何受到CSF-1/c-FMS的负调控 髓系细胞系中酪氨酸激酶信号转导途径的研究 这种调节发生在破骨细胞中。这些研究将被执行 在三个实验系统中：异种细胞系，原代 破骨细胞样细胞体外培养，体内转基因小鼠和 遗传模型。这些信息将提出具体的战略建议 干扰破骨细胞的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.