GENETIC ANALYSIS OF BONE MORPHOGENETIC PROTEINS

这项研究的长期目标是定义分子 控制软骨生长和形态的机制， 骨头和关节。这是一个普遍的问题，在…的发展中 更高级的动物，尤其与 对人类骨骼疾病的认识和治疗， 包括骨质疏松症和骨性关节炎。这些研究是 特别是为了理解骨骼的作用 发育正常的形态发生蛋白(BMPs)。BMPS 最初是基于它们非凡的能力而被孤立的 植入后诱导新骨形成和骨形成 动物的皮肤。脊椎骨基因组包含10个或 更多的BMP基因，每个都以不同的模式在 正常发育。许多密切相关的基因被发现存在于 其他生物体，在那里它们控制着各种各样的功能， 包括轴的形成、组织分化和上皮- 间充质相互作用。虽然BMP现在被认为是 动物体内信号分子的关键类别之一 发展，大量不同的BMP及其 多重功能，阻碍了对它们在 骨骼发育。我们最近展示了两个经典的 小鼠的基因(短耳和短足)编码两种不同的基因 BMP家族的成员。这些基因的缺陷会产生 令人惊讶的特殊变化，特别是骨骼和软骨 元素，特别是关节。基于突变体 这些基因的表型和表达模式，我们有 提出BMP是人类使用的内源性信号 胚胎诱导骨骼和关节的形成，以及 BMP家族的不同成员控制着形成 不同的骨骼结构的集合。为了测试这个模型，我们 将使用两种不同的遗传策略来检查功能 其他BMP在小鼠发育中的作用。占主导地位的负数 Nutaton将用于在特定情况下灭活多个BMP 骨骼组织。两个新的BMP中的已知基因突变将是 用来测试不同的BMP是否控制了 不同类型的关节。最后，我们将使用转基因小鼠和 定义顺式和反式作用的新的调控突变 控制何时何地特定骨骼和关节的因素 诱导信号在正常发育过程中表达。 这些研究将为基础生物学提供新的见解。 创建骨骼和关节的机制，新工具 控制骨骼中特定位置的基因表达，以及 可能提出新的策略来调控BMP的表达 人类骨骼疾病。

The long term goal of this research is to define the molecular mechanisms that control growth and patterning of cartilage, bone, and joint. This is a general proble, in the developent of higher animals, and is of particular relevance to the understanding and treatment of human skeletal diseases, including osteoporosis and osteoarthritis. The studies are specifically directed to understanding the role of bone morphogenetic proteins (BMPs) in normal development. BMPs were originally isolated based on their remarkable ability to induce new caritlage and bone formation when implanted under the skin of animals. The vertebrae genome contains ten or more BMP genes, each expressed in different patterns during normal development. Closely related genes are found in many other organisms, where they control a wide variety of functions, including axis formation, tissue differentiation, and epithelial- mesenchymal interactions. While BMPs are now recognized as one of key classes of signalling molecules in animal development, the large number of different BMPs, and their multiple functions, has hampered studies of their specific role in skeletal development. We have recently shown that two classical mouse genes (short ear and brachypodism) encode two different members of the BMP family. Defects in these genes produce surprisingly specific alterations in particular bone and cartilage elements, and in particular joints. Based on the mutant phenotypes and wxpression patterns of these genes, we have proposed that bMps are the endogenous signals used by embryos to induce the formation of both bones and joints, and that different members of the BMP family control the formation of different sets of skeletal structures. To test this model, we will use two different genetic strategies to examine the functions of other Bmps in mouse development. A dominant negative nutaton will be used to inactivate multiple BMPs in specific skeletal tissues. Knowckout mutations in two new Bmps will be used to test whether different BMPs control formation of different types of joints. Finally, we will use transgenic mice and novel regulatory mutations to define the cis and trans acting factors that control where and when particular bone and joint inducing signals are expressed during normal development. These studies will provide new insights into the basic biological mechanisms that create bones and joints, new tools for maipulating gene expression at specific sites in the skeleton, and may suggest novel strategies for modulating BMP expression in human skeletal diseases.