MORPHOGENETIC CONTROL OF CARTILAGE AND BONE DEVELOPMENT

描述：（直接取自申请）了解导致正常骨形成的分子和细胞事件是理解人类骨骼疾病病因学的必要先决条件。此外，它可能提供见解，将允许设计新的治疗方法来治疗病理性或意外损伤的骨骼。软骨内骨骼的发育受多种信号因子介导的细胞间相互作用调控，这些信号因子包括wnt、转化生长因子- β (TGF-B)超家族成员、刺猬、PTHrP和成纤维细胞生长因子（fgf）。本应用程序的目的是确定软骨形态发生的几个关键分泌调节因子的作用，并检查这些因子如何在软骨和骨发育中相互作用。这将在遗传学研究中完成，这些研究将利用携带信号因子、其潜在调节因子或其潜在靶标的零突变或功能转基因的小鼠。具体目标1将确定Ihh通过PTHrP途径调节软骨形态发生的程度，并将解决Ihh信号在骨和软骨发育中的细胞自主和潜在的非细胞自主作用。Specific Aim 2旨在测试Ihh是否介导Hoxa-11和Hoxd-11在尺骨和桡骨中的生长调节作用。特异性目的3研究了Noggin（一种假定的BMP拮抗剂）和BMP4在轴向骨架形成过程中可能的遗传相互作用。特异性目标4阐述了Wnt 5a调节肢体近端-远端生长和近端软骨元件生长的分子机制。

Description: (Taken directly from the application) Understanding the molecular and cellular events which lead to normal bone formation is an essential prerequisite for understanding the etiology of skeletal disorders in man. Further, it may provide insights which will permit the design of new therapeutic approaches for treating pathological or accidental damage to the skeleton. Development of the endochondral skeleton is regulated by cell-cell interactions mediated by members of several signaling factors including Wnts, transforming growth factor-beta (TGF-B) superfamily members, Hedgehogs, PTHrP, and fibroblast growth factors (FGFs). The goal of this application is to establish the role of several key secreted regulators of cartilage morphogenesis and to examine how these factors interact in cartilage and bone development. This will be done in genetic studies which utilize mice carrying either null mutations or gain of function transgenes in signaling factors, their potential regulators or their potential targets. Specific Aim 1 will determine the extent to which Ihh regulates cartilage morphogenesis through the PTHrP pathway and will address the cell autonomous and potential non-cell autonomous action of Ihh signaling in bone and cartilage development. Specific Aim 2 sets out to test whether Ihh may mediate the growth-regulating action of Hoxa-11 and Hoxd-11 in the ulna and radius. Specific Aim 3 examines the possible genetic interactions between Noggin, a putative BMP antagonist, and BMP4, in forming the axial skeleton. Specific Aim 4 addresses the molecular mechanisms by which Wnt 5a regulates proximo-distal outgrowth of the limb and growth of proximal cartilage elements.