Mechanisms of Synovial Joint Formation

滑膜关节形成机制

• 批准号: 7413662
• 负责人: Maurizio Pacifici
• 金额: $ 36.91万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7413662
• 关键词: AXIN2 protein; Ablation; Affect; Aging; Animals; Appearance; Area; Cells; Chondrocytes; Chondrogenesis; Clear Cell; Condition; Data; Defect; Development; Digit structure; Distal; Dyes; Embryo; Embryonic Development; Employee Strikes; Failure; Future; Genes; Growth; Human; Individual; Joint by Site; Joints; Life; Ligaments; Limb structure; Location; Maintenance; Maps; Mesenchymal; Morphogenesis; Mus; Mutation; Partner in relationship; Pathway interactions; Patients; Pattern; Phenotype; Procedures; Process; Property; Quality of life; Reporter; Research Personnel; Role; Shapes; Side; Signal Transduction; Signaling Protein; Skeletal system; Skeleton; Staging; Stem cells; Structure; Synovial Membrane; Testing; Thick; Thinking; Time; Tissue Donors; Tissues; Transgenes; Work; aging population; articular cartilage; base; chordin; fetal; insight; interest; loss of function; novel; programs; promoter; recombinase; repaired; research study

DESCRIPTION (provided by applicant): Synovial joints are critical for skeletal function, but we remain surprisingly ignorant about how they actually form during fetal life. In the limb, joint development starts with appearance of a mesenchymal interzone at future joint sites. Interzone progenitor cells are thought to give rise to tissues including articular cartilage and participate in joint morphogenesis, but it is not clear how the cells perform these critical tasks. The signaling proteins GDF-5 and Wnt-14 are strongly expressed by early interzone. GDF-5 was found to act as a growth and interzone determination factor, while Wnt-14 acted as an upstream regulator of interzone/early joint genes, including GDF-5 itself, Chordin and CD-44. In preliminary work we show for the first time that: Wnt-14 and GDF-5 are expressed in distinct patterns during interzone formation; peri-joint mesenchymal cells migrate into nascent interzone; GDF-5 expression becomes restricted to convex side during joint morphogenesis; and Wnt-14 signaling involves b-catenin. Our central hypotheses are: (i) interzone is made of progenitor cells derived from peri-joint sites; and (ii) GDF-5 and Wnt-14 have distinct, but interrelated roles during interzone and joint formation and morphogenesis. Our aims are to establish origin and fate maps of interzone cells, determine GDF-5 and Wnt-14 roles and mechanisms of action, and create conditionally Wnt-14-ablated mice and assess consequences. We will use cell tracing-tracking procedures, including ROSA reporter mice mated with available GDF-5-Cre mice; chimeric-microsurgical approaches; and Wnt-14 and GDF-5 gain- and loss-of-function approaches on chick and mouse autopods (paws), including those isolated from available GDF-5-null brachypodism mice and b-catenin-dependent axin-2 promoter reporter mice. The project will generate fundamental information on mechanisms of joint formation. The results will be invaluable in conceiving novel, directed and specific therapies to repair and restore malfunctioning joints common to aging individuals and otherwise affected patients.

描述（由申请人提供）：滑膜关节对于骨骼功能至关重要，但我们仍然对它们在胎儿生活中的实际形式无知。在肢体中，关节发育始于在未来的关节部位的间充质间间的出现。认为倍数间的祖细胞被认为会引起包括关节软骨在内的组织并参与关节形态发生，但尚不清楚细胞如何执行这些关键任务。信号蛋白GDF-5和WNT-14由早期间Zone强烈表达。发现GDF-5充当生长和间区域的测定因子，而Wnt-14充当了Interzone/早期关节基因的上游调节剂，包括GDF-5本身，Chordin和CD-44。在初步工作中，我们首次表明：Wnt-14和GDF-5在间区间组中以不同的模式表达；间充质细胞迁移到新生的间斑中；在关节形态发生过程中，GDF-5表达被限制在凸面。 WNT-14信号传导涉及B-catenin。我们的中心假设是：（i）间zone由衍生自联合部位的祖细胞制成； （ii）GDF-5和WNT-14具有独特的，但在间区域和关节形成和形态发生过程中相互关联的作用。我们的目的是建立间区域细胞的起源和命运图，确定GDF-5和WNT-14作用和作用机理，并创建有条件地有WNT-14驱动的小鼠并评估后果。我们将使用细胞跟踪跟踪程序，包括与可用的GDF-5-CRE小鼠配合的Rosa Reporter小鼠；嵌合微神经方法；以及小鸡和小鼠自动脚架（PAWS）的WNT-14和GDF-5增益和功能丧失方法，包括从可用的GDF-5-5-NULL腕足小鼠中分离出的那些小鼠和B-catenin依赖性AXIN-2启动子报告子小鼠。该项目将生成有关联合形成机制的基本信息。在构想新颖，定向和特定的疗法方面，该结果将是无价的，以修复和恢复老龄化个体和其他影响患者共有的关节不良关节。