Type III Collagen Gene Expression in Cartilage

软骨中 III 型胶原基因的表达

• 批准号: 6890488
• 负责人: SHERRILL L. ADAMS
• 金额: $ 33.52万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-07-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6890488
• 关键词: articular cartilage; biomechanics; cartilage development; chick embryo; chondrocytes; collagen; cytokine; extracellular matrix; gene expression; genetic promoter element; genetic regulation; genetic transcription; genetically modified animals; histogenesis; histology; hydrostatic pressure; interleukin 1; intervertebral disk; laboratory mouse; limbs; mesenchyme; messenger RNA; protein biosynthesis; site directed mutagenesis; tissue /cell culture

DESCRIPTION (provided by applicant): The chick type III collagen gene produces two unrelated proteins, type III collagen and a small non-collagenous protein, Col3alt. The upstream promoter of this gene directs production of type III collagen mRNA and protein, while an internal promoter directs production of an alternative transcript that produces Col3alt. This gene displays a complex pattern of regulation during chondrogenesis and in cartilage pathology. Type Ill collagen is produced in prechondrogenic mesenchymal cells, but is not present in embryonic cartilages. However, type III collagen is found in adult articular cartilages and in the cartilage-like structures of the intervertebral disk. The amount of type III collagen is increased significantly in osteoarthritis and degenerative disk disease, and is induced in cultured chondrocytes by treatment with interleukin 1, a pro-inflammatory cytokine that plays an important role in osteoarthritis. Col3alt, the product of the alternative transcript of the type III collagen gene, is produced in prechondrogenic mesenchyme along with type III collagen; however, production of Col3alt continues in embryonic cartilages and in juvenile growth plates, where it is secreted into the matrix. The regulation of this gene and the functions of its two products will be investigated in the following specific aims: 1) Characterize the transcriptional mechanisms regulating cessation of type III collagen production during chondrogenesis; 2) Determine whether type III collagen gene expression is reactivated in chondrocytes in response to hydrostatic pressure and proinflammatory cytokines and identify the mechanisms responsible for reactivation; 3) Determine the role of type III collagen in the cartilage matrix and its function in the intervertebral disc; and 4) Examine the hypothesis that Col3alt is required for chondrogenesis, by modulating its production during in vitro and in vivo limb development. The proposed experiments will strengthen our understanding of the regulation and function of the type III collagen gene during chondrogenesis and in response to stress and proinflammatory cytokines, and will define the roles of type III collagen in cartilage and intervertebral disc and the function of Col3alt in chondrogenesis. Finally, these studies will provide unique insights into the regulation of a complex locus which is, in essence, a gene within a gene.

描述（由申请人提供）：III型胶原蛋白基因产生两种无关的蛋白质，即III型胶原蛋白和一个小的非胶原蛋白Col3alt。该基因的上游启动子指导III型胶原mRNA和蛋白质的产生，而内部启动子则指导产生产生Col3alt的替代转录本的产生。该基因在软骨发生和软骨病理学期间显示出复杂的调节模式。型胶原蛋白是在质子性间充质细胞中产生的，但在胚胎软骨中不存在。但是，在成人关节软骨和椎间盘的软骨样结构中发现了III型胶原蛋白。 III型胶原蛋白的量在骨关节炎和退化性椎间盘疾病中显着增加，并通过用白介素1治疗培养的软骨细胞诱导，这是一种促炎性细胞因子，在骨关节炎中起着重要作用。 Col3alt是III型胶原蛋白基因的替代转录物的乘积，是在近代的间充质中与III型胶原蛋白一起产生的。然而，在胚胎软骨和少年生长板中，Col3alt的生产仍在继续，在此分泌到基质中。该基因的调节及其两种产物的功能将在以下具体目的中进行研究：1）表征调节软骨发生过程中III型胶原蛋白产生的停止的转录机制； 2）确定是否响应静水压力和促炎细胞因子，在软骨细胞中重新激活III型胶原蛋白基因表达，并确定导致重新激活的机制； 3）确定III型胶原蛋白在软骨基质中的作用及其在椎间盘中的功能； 4）检查了软骨发生所需的假设，即通过调节体外和体内肢体发育过程中的产生。提出的实验将加强我们对软骨生成过程中III型胶原基因的调节和功能的理解，并响应压力和促炎细胞因子，并将定义III型collagen在软骨和椎间盘椎间盘的作用以及Col3alt在软骨生成中的作用。最后，这些研究将提供独特的见解，以调节复杂基因座的调节，这本质上是基因中的基因。