BMP'S IN SKELETAL GROWTH AND OSTEOGENESIS

描述（改编自研究者摘要）：骨形态发生 蛋白质（BMP）是软骨和骨形成的重要调节因子， 了解它们在骨骼组织中的功能对于 有效的骨骼维护和修复疗法。的表达 骨骼组织中的多种BMP表明这些配体可能 重叠的功能和/或不同的成员在软骨中发挥不同的作用， 和骨头。最近的研究支持每一种可能性，并提出了 另外的复杂性是单一的BMP配体可以具有不同的作用， 这取决于它所结合的受体。BMP作用的特异性是 这被认为部分是通过BMP配体对 三种I型BMP受体之一。此外，单个BMP通过 单一类型的受体可能有不同的影响，这取决于水平， 受体激活因此，虽然体外研究已经被用于 有利的是限定可由BMP调节的活性范围， 确定这些生长因子在软骨中的生理作用， 骨只能通过体内研究获得。体内研究使用 缺乏BMP受体的小鼠品系形成了该建议的基础。 BmprIB缺陷小鼠和携带BmprII亚型等位基因的小鼠 （BmprIIdeltaE2）。特别地，BmprII-/-小鼠发生严重的 骨关节炎，允许分析BMP信号通路在骨关节炎中的作用。 体内关节软骨。拟议的研究将利用携带 BmprIA的“floxed”等位基因（BmprIAfx），其允许该基因被消除 在软骨中使用Cre/loxP技术，以测试BmprIA和 BmprIB在体内表现出重叠和独特的功能。所有菌株 需要测试这个假设已经获得。主要研究者 还将产生携带ActrI的floxed等位基因的小鼠，以测试 假设这种受体在骨骼肌中具有独特和必要的功能， 组织中最后，BmprII deltaE 2/deltaE 2小鼠，它们是纯合的a 假定的亚纯型（简化功能）等位基因，表现出轴向缺陷 整个骨骼的模式化和延迟的骨生成。校长 研究者将使用Cre/lox生成BmprII的floxed无效等位基因 技术.由此产生的等位基因系列将用于检验假设 不同水平的受体激活会导致不同的细胞反应 在软骨中。这些实验很可能揭示出以前未被怀疑的 BMP信号通路在软骨中的作用，并导致更具体的， 有效的治疗方法，如骨关节炎。

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.