Zinc Finger Protein Zac1 and Chondrogenesis

描述(申请人提供)：本申请的长期目标是了解软骨形成和修复的分子和细胞机制。关节软骨的退化导致骨关节炎(OA)，这是影响中老年人的最常见的关节炎形式。软骨丧失至少部分是由于软骨细胞不能修复软骨基质和软骨细胞增殖能力降低所致。然而，调控软骨细胞增殖及其生物合成活性的机制却知之甚少。申请人发现，Zacl是一种最近表征的锌指蛋白，在小鼠胚胎发育过程中主要定位于发育中的软骨组织中。ZACL具有抗增殖活性，是一种潜在的肿瘤抑制基因，提示其可能对软骨细胞的增殖分化和软骨基因的表达具有调控作用。本申请提出利用已建立的软骨细胞分化的体外模型培养体系来研究ZACL在软骨形成中的作用。我们将研究Zacl在体外软骨形成过程中的过度表达和抑制作用，以及Zacl在软骨细胞分化过程中的调控基因。这些研究将提供对软骨形成和修复的重要调控因素的更好的理解。

DESCRIPTION (provided by applicant): The long-term objective of this application is to understand the molecular and cellular mechanisms underlying cartilage formation and repair. Degeneration of the joint cartilage leads to osteoarthritis (OA), the most common form of arthritis affecting middle-aged and elderly people. The cartilage loss is caused, at least in part, by the failure of chondrocytes to repair the cartilage matrix and reduced proliferative capacity of the chondrocytes. The mechanisms that regulate chondrocyte proliferation and its biosynthetic activity, however, are poorly understood. The applicant has found that Zacl, a recently characterized zinc finger protein, is predominantly localized in the developing chondrogenic tissue during mouse embryogenesis. Zacl possesses anti-proliferative activity and is a potential tumor suppressor gene, suggesting that it may have a role in regulating chondrocyte proliferation and differentiation, and cartilage gene expression. This application proposes to investigate the role of Zacl in chondrogenesis using an established in vitro model culture system for chondrocyte differentiation. The effects of over-expression and inhibition of Zacl during in vitro chondrogenesis will be studied, and the genes regulated by Zacl in chondrocyte differentiation will be investigated. These studies will provide a better understanding of regulatory factors important for cartilage formation and repair.