The role of the kimble gene in regulating craniofacial morphogenesis

描述(申请人提供)：软骨细胞死亡是许多退行性软骨疾病的中心组成部分，如骨关节炎和颞下颌关节紊乱病，因此对公众健康有重大影响。通过研究一个头部骨骼畸形的斑马鱼突变体，该项目发现胞吐功能受损是脑颅和咽弓内软骨细胞凋亡和软骨退化的潜在新机制，导致筛板裂开。在这个突变体中，软骨降解的开始发生在最初的软骨沉积之后。因此，这种突变会破坏软骨的维持，但不会破坏软骨的形成，并且在进展过程中类似于某些形式的骨关节炎和其他退行性软骨疾病。通过使用正向遗传学和位置克隆，该方法还发现了一个新的基因，对颅面发育和软骨细胞生存是必要的。该项目的目标是a)确定该基因对软骨细胞的生存是细胞自主还是非细胞自主所必需的，以及b)确定该基因功能丧失导致软骨细胞死亡的机制。测试该基因的细胞自主功能的方法将包括使用斑马鱼遗传学和细胞移植实验。机械学研究还将使用活体分析和成像方法。通过探索这个新基因在颅面形态发生中的作用，本项目确定了导致软骨细胞死亡和软骨退化的新机制。这些重要发现突显了进一步研究动物模型的重要性。在拟议的研究过程中获得的发现可能会对退行性软骨疾病的病理生理学产生重要的翻译影响。此外，由于这里分析的斑马鱼突变表型会导致脑颅裂开，这些研究结果可能会提供先天性口面部裂伤与成人软骨疾病之间的联系。 公共卫生相关性：软骨细胞死亡是许多退行性软骨疾病的中心组成部分，如骨关节炎和颞下颌关节紊乱病，因此对公共健康有重大影响。通过探索一个新基因在颅面形态发生过程中的功能，本项目确定了导致软骨细胞死亡和软骨退化的新机制，这一过程类似于某些形式的人类退行性软骨疾病。

DESCRIPTION (provided by applicant): Chondrocyte cell death is a central component of many degenerative cartilage diseases, such as osteoarthritis and temporomandibular joint disorders, and thus has a substantial public health impact. By investigating a zebrafish mutant with a malformed head skeleton, this project has identified impaired exocytosis as a potentially novel mechanism of chondrocyte apoptosis and cartilage degradation within the neurocranium and pharyngeal arches, leading to clefting of the ethmoid plate. In this mutant, the onset of cartilage degradation develops after initial cartilage deposition. Thus, this mutation disrupts the maintenance but not the formation of cartilage and is similar in progression to some forms of osteoarthritis and other degenerative cartilage diseases. Through the use of forward genetics and positional cloning, this approach has also identified a novel gene necessary for craniofacial development and chondrocyte cell survival. The goals of this project are a) to identify whether this gene is required cell-autonomously or non cell-autonomously for chondrocyte cell survival and b) to define the mechanism by which loss of this gene function leads to chondrocyte cell death. Approaches for testing the cell autonomous function of this gene will include the use of zebrafish genetics and cell transplantation experiments. Mechanistic studies will also use in vivo analyses and imaging approaches. By exploring the function of this novel gene during craniofacial morphogenesis, this project identifies a new mechanism leading to chondrocyte cell death and cartilage degradation. These key discoveries highlight the importance of further studies in animal models. Findings obtained during the course of the proposed study may have important translational impact with respect to the pathophysiology of degenerative cartilage diseases. Moreover, because the zebrafish mutant phenotype analyzed here leads to clefting of the neurocranium, the results of these studies may provide a link between congenital orofacial clefts and adult cartilage diseases. PUBLIC HEALTH RELEVANCE: Chondrocyte cell death is a central component of many degenerative cartilage diseases, such as osteoarthritis and temporomandibular joint disorders, and thus has a substantial public health impact. By exploring the function of a novel gene during craniofacial morphogenesis, this project identifies a new mechanism leading to chondrocyte cell death and cartilage degradation, a progression which mimics some forms of human degenerative cartilage diseases.