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The role of the kimble gene in regulating craniofacial morphogenesis

kimble基因在调节颅面形态发生中的作用

基本信息

批准号：
8203109
负责人：
Daniel S Levic
金额：
$ 2.72万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8203109
关键词：
Ablation Adhesions Adult Affect Animal Model Antibodies Apoptosis Apoptotic Appearance Arthritis Biological Assay Branchial arch structure Cartilage Cartilage Diseases Cell Adhesion Cell Death Cell Survival Cell Transplantation Cell Transplants Cell membrane Cell physiology Cells Chondrocytes Cleaved cell Cleft Palate Collagen Collagen Type II Congenital Disorders Cytoplasmic Vesicles Data Degenerative Disorder Degenerative polyarthritis Deposition Development Disease Electron Microscopy Exocytosis Extracellular Matrix Family member Fibronectins Functional disorder Genes Genetic Goals Golgi Apparatus Head Hela Cells Human Image Analysis Immunohistochemistry Integrins Lead Link Maintenance Maxillary Prominence Mediating Membrane Modeling Morphogenesis Mutate Mutation Neural Crest Cell Nonsense Mutation Palate Phenotype Protein Secretion Proteins Public Health Recycling Research Design Role Signal Transduction Skeleton Staging Temporomandibular Joint Disorders Temporomandibular joint osteoarthritis Testing Tissues Transplantation Transport Vesicles VAMP-2 Vesicle Zebrafish cartilage development cell type craniofacial cytotoxic gene function in vivo insight migration mutant novel orofacial positional cloning prevent promoter research study vesicular SNARE proteins

项目摘要

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.

描述（由申请人提供）：软骨细胞死亡是许多退行性软骨疾病的核心组成部分，如骨关节炎和颞下颌关节疾病，因此具有重大的公共卫生影响。通过研究头部骨骼畸形的斑马鱼突变体，该项目已经确定了胞吐功能受损是神经头盖骨和咽弓内软骨细胞凋亡和软骨降解的潜在新机制，导致筛板开裂。在这个突变体中，软骨退化发生在最初的软骨沉积之后。因此，这种突变破坏了软骨的维持，但没有破坏软骨的形成，其进展与某些形式的骨关节炎和其他退行性软骨疾病相似。通过使用正向遗传学和定位克隆，这种方法也确定了颅面发育和软骨细胞存活所必需的新基因。该项目的目标是a)确定该基因是细胞自主还是非细胞自主地需要软骨细胞存活，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。机制研究也将使用体内分析和成像方法。通过探索该新基因在颅面形态发生中的功能，本项目确定了导致软骨细胞死亡和软骨降解的新机制。这些关键的发现突出了在动物模型中进一步研究的重要性。在拟议的研究过程中获得的发现可能对退行性软骨疾病的病理生理学有重要的转化影响。此外，由于这里分析的斑马鱼突变表型导致神经头盖骨裂，这些研究的结果可能提供先天性口面裂与成人软骨疾病之间的联系。