MORPHOGENETIC CONTROL OF CARTILAGE AND BONE DEVELOPMENT

描述：(直接取自本申请)了解导致正常骨形成的分子和细胞事件是了解人类骨骼疾病病因学的基本前提。此外，它可能提供洞察力，允许设计新的治疗方法来治疗骨骼的病理或意外损伤。软骨内骨骼的发育受多种信号因子的细胞间相互作用的调节，这些信号因子包括WNTS、转化生长因子-β超家族成员、Hedgehog、PTHrP和成纤维细胞生长因子(FGFs)。这项应用的目的是确定软骨形态发生的几个关键的分泌性调节因素的作用，并研究这些因素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，该研究利用在信号因子、其潜在调节器或其潜在靶标中携带零突变或获得功能转基因的小鼠。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，并将阐述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。具体目标2旨在测试IHH是否可能介导Hoxa-11和Hoxd-11在尺骨和桡骨的生长调节作用。特异性目标3研究了BMP拮抗剂Noggin和BMP4在形成中轴骨架过程中可能的遗传相互作用。具体目的4阐述Wnt5a调节肢体近端-远端突起和近端软骨元素生长的分子机制。

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.