GENETIC ANALYSIS OF BONE MORPHOGENETIC PROTEINS

这项研究的长期目标是确定 控制软骨生长和形成的机制， 骨和关节。 这是一个普遍性的问题， 高等动物，特别是与 了解和治疗人类骨骼疾病， 包括骨质疏松症和骨关节炎。 这些研究 特别是为了了解骨骼的作用 形态发生蛋白（BMP）在正常发育中的作用。 BMPs 最初被隔离是因为它们具有非凡的能力， 当植入时诱导新软骨和骨形成 动物的皮肤。 椎骨基因组包含十个或 更多的BMP基因，每一个都以不同的模式表达， 正常发展。 在许多动物中发现了密切相关的基因， 其他生物体，它们控制着各种各样的功能， 包括轴形成、组织分化和上皮- 间充质相互作用 虽然BMP现在被认为是 动物体内的一种关键信号分子 发展，大量不同的BMP，及其 多种功能，阻碍了对它们在 骨骼发育我们最近证明了两个经典的 小鼠基因（短耳和短足）编码两种不同的 BMP家族的成员。 这些基因的缺陷会产生 特别是骨和软骨中令人惊讶的特异性改变 元件，特别是接头。 根据变种人 这些基因的表型和表达模式，我们有 提出bMps是内源性信号， 胚胎以诱导骨骼和关节的形成，以及 BMP家族的不同成员控制着 不同的骨骼结构。 为了验证这个模型，我们 将使用两种不同的遗传策略来研究 在小鼠发育中的作用。 显性失活 nutaton将用于在特定的条件下， 骨骼组织 两种新BMPs的敲除突变将被 用于测试不同的BMP是否控制 不同类型的关节。 最后，我们将使用转基因小鼠， 定义顺式和反式作用的新调控突变 控制特定骨骼和关节的位置和时间的因素 诱导信号在正常发育过程中表达。 这些研究将提供新的见解，基本的生物学 创建骨骼和关节的机制， 操纵骨骼中特定位点的基因表达， 可能提出了调节BMP表达的新策略， 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.