BMP'S IN SKELETAL GROWTH AND OSTEOGENESIS

描述(改编自调查者摘要)：骨形态发生 蛋白质(BMPs)是软骨和骨形成的重要调节因子，以及 了解它们在骨骼组织中的功能对发育至关重要。 有效的骨骼维护和修复疗法。的表达方式 骨骼组织中的多个BMP表明这些配体可能起作用 重叠的功能和/或不同的成员在软骨中扮演不同的角色 还有骨头。最近的研究支持每一种可能性，并提出了 单个BMP配体可以具有不同效果的额外复杂性， 这取决于它所结合的受体。BMP作用的特异性是 被认为部分是通过BMP配体的不同亲和力实现的 三种I型骨形态发生蛋白受体之一。此外，单个BMP通过 单一类型的受体可能有不同的作用，这取决于 受体激活。因此，虽然体外研究被用来很好地 定义可由BMP管理的活动范围的优点， 确定这些生长因子在软骨和软骨中发挥的生理作用 只有通过体内研究才能获得骨骼。体内研究利用 缺乏BMP受体的小鼠品系构成了这一提议的基础。 BmprIB缺陷小鼠和携带BmprII亚型等位基因的小鼠 (BmprIIdeltaE2)将被利用。特别是，BmprII-/-小鼠发展为严重的 骨关节炎，允许分析BMP信号通路在骨关节炎中的作用 活体关节软骨。这项拟议的研究将利用携带有 BmprIA(BmprIAfx)的“花”等位基因，它允许该基因被消除 在软骨中使用Cre/loxP技术，以检验BmprIA和BmprIA BmprIB在体内具有重叠和独特的功能。所有的菌株 检验这一假说所需的数据已经得到证实。首席调查员 也将产生携带ActrI的等位基因的小鼠来测试 该受体在骨骼中具有独特和基本功能的假说 纸巾。最后，BmprIIdeltaE2/deltaE2小鼠是纯合子的 推测为亚形态(功能减退)等位基因，表现出轴向缺陷 整个骨骼的图案化和延迟的成骨。《校长》 研究人员将使用CRE/LOX生成BmprII的无效等位基因 技术产生的等位基因序列将被用来检验这一假设 不同水平的受体激活会导致不同的细胞反应 在软骨里。这些实验很可能会揭开之前未曾发现的疑点 BMP信号通路在软骨中的作用，并导致更特异和 治疗骨关节炎等疾病的有效疗法。

DESCRIPTION (Adapted from the Investigator's Abstract): Bone Morphogenetic Proteins (BMPs) are essential regulators of cartilage and bone formation, and understanding their functions in skeletal tissues is crucial to the development of effective therapies for skeletal maintenance and repair. The expression of multiple BMPs in skeletal tissues suggests that these ligands may serve overlapping functions and/or different members play distinct roles in cartilage and bone. Recent studies support each of these possibilities, and raise the additional complexity that a single BMP ligand can have diverse effects, depending on the receptor to which it binds. Specificity of BMP action is thought to be achieved in part by differential affinities of BMP ligands for one of three type I BMP receptors. Moreover, a single BMP acting through a single type of receptor may have diverse effects, depending on the level of receptor activation. Thus, while in vitro studies have been used to great advantage to define the range of activities that can be regulated by BMPs, identifying the physiological roles these growth factors play in cartilage and bone can only be achieved through in vivo studies. In vivo studies utilizing strains of mice deficient in BMP receptors form the basis of this proposal. Mice deficient in BmprIB, and mice carrying a hypomorphic allele of BmprII (BmprIIdeltaE2) will be utilized. In particular, BmprII-/- mice develop severe osteoarthritis, permitting an analysis of the role of BMP signaling pathways in articular cartilage in vivo. The proposed studies will utilize mice carrying a "floxed" allele of BmprIA (BmprIAfx), which allows this gene to be eliminated in cartilage using Cre/loxP technology, to test the hypothesis that BmprIA and BmprIB exhibit overlapping and unique functions in vivo. All of the strains needed to test this hypothesis have been obtained. The Principal Investigator will also generate mice carrying a floxed allele of ActrI to test the hypothesis that this receptor has unique and essential functions in skeletal tissues. Finally, BmprIIdeltaE2/deltaE2 mice, which are homozygous for a putative hypomorphic (reduced function) allele, exhibit defects in axial patterning and delayed osteogenesis throughout the skeleton. The Principal Investigator will generate a floxed null allele of BmprII using Cre/lox technology. The resulting allelic series will be used to test the hypothesis that different levels of receptor activation cause different cellular responses in cartilage. These experiments are likely to uncover previously unsuspected roles for BMP signaling pathways in cartilage, and to lead to more specific and effective therapies for diseases such as osteoarthritis.