Gene Regulation and Function of Cartilage

软骨的基因调控和功能

• 批准号: 6432015
• 负责人: Yoshihiko Yamada
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6432015
• 关键词: bone development; cartilage; cartilage development; chondrocytes; craniofacial; developmental genetics; extracellular matrix; gene induction /repression; gene mutation; human genetic material tag; link protein; neoplasm /cancer genetics; oral pharyngeal neoplasm; tissue /cell culture; tooth

Cartilage is a highly specialized connective tissue with distinct morphological and biochemical characteristics. It contains an extensive extracellular matrix and provides mechanical strength to resist compression in joints. In development, cartilage serves as the template for the growth and development of most bones. When cartilage formation is impaired, skeletal malformation of the limbs, craniofacial bones, and appendicular skeleton occurs. Chondrocytes produce large amounts of cartilage-specific matrix molecules, including type II collagen, aggrecan, link protein, and hyaluronan. Cartilage development is initiated by mesenchymal cell condensation to form primordial cartilage followed by chondrocyte maturation. These include resting, proliferative, prehypertrophic, and hypertrophic chondrocytes. As a final step in endochondral bone formation, hypertrophic cartilage is invaded by blood vessels and osteoprogenitor cells, and the calcified cartilage is subsequently replaced by bone. Thus, spatial and temporal regulation of chondrocyte differentiation is essential in determining the length and width of skeletal components. Hormones and vitamins affect cartilage development and maturation by regulating the transcription of genes. Our objective is to define the mechanisms for activating chondrocyte-specific genes and to elucidate the molecular basis of cartilage development. Using an animal model, we also study the function of cartilage proteins in vivo. We initiated the Oral and Craniofacial Genome Anatomy Project (OC-GAP) to identify novel genes important for tooth and craniofacial development. Our goal is to discover and characterize previously unknown genes to help understand how tooth and craniofacial tissues develop and to define the molecular defects underlying anomalies of these tissues or oral cancer. Craniofacial anomalies of the mouth, neck, and head are of major public concern. A large number of genes are involved in such anomalies and cancers. As an initial step, we have started to identify and catalogue the genes involved in specific stages of tooth and craniofacial development. The identification of genes that have highly location- and stage-specific expression is important since the gene products are likely to have key roles in the formation of craniofacial tissues. It is also expected that mutations in these genes cause anomalies. This information will also be useful for generating diagnostic reagents, developing methods for disease and birth defect prevention, and for potential gene therapies.

软骨是一种高度专业化的结缔组织，具有明显的形态和生化特征。它含有广泛的细胞外基质，并提供抵抗关节压缩的机械强度。在发育过程中，软骨是大多数骨骼生长和发育的模板。当软骨形成受损时，就会出现四肢、头面部骨骼和附件骨骼的骨骼畸形。软骨细胞产生大量的软骨特异性基质分子，包括II型胶原、聚集素、连接蛋白和透明质酸。软骨发育始于间充质细胞凝聚形成原始软骨，随后软骨细胞成熟。这些细胞包括静止期、增殖期、增生期前期和增生期软骨细胞。作为软骨内骨形成的最后一步，肥大的软骨被血管和骨祖细胞侵袭，钙化的软骨随后被骨取代。因此，软骨细胞分化的空间和时间调节在决定骨骼成分的长度和宽度方面是必不可少的。激素和维生素通过调节基因转录来影响软骨的发育和成熟。我们的目标是明确激活软骨细胞特异性基因的机制，并阐明软骨发育的分子基础。利用动物模型，我们还研究了软骨蛋白在体内的功能。我们发起了口腔和颅面基因组解剖计划(OC-GAP)，以确定对牙齿和颅面发育至关重要的新基因。我们的目标是发现和鉴定以前未知的基因，以帮助了解牙齿和颅面组织是如何发展的，并确定这些组织异常或口腔癌潜在的分子缺陷。口腔、颈部和头部的颅面畸形是公众主要关注的问题。这种异常和癌症涉及大量的基因。作为第一步，我们已经开始对牙齿和颅面发育的特定阶段涉及的基因进行识别和分类。识别具有高度位置和阶段特异性表达的基因是重要的，因为基因产物可能在头面部组织的形成中起关键作用。人们还预计，这些基因的突变会导致异常。这些信息也将有助于开发诊断试剂，开发预防疾病和出生缺陷的方法，以及潜在的基因疗法。