Reciprocal Signaling In Skeletogenesis

骨骼发生中的相互信号传导

基本信息

批准号：
7891321
负责人：
CHARLES B KIMMEL
金额：
$ 44.81万
依托单位：
UNIVERSITY OF OREGON
依托单位国家：
美国
项目类别：
财政年份：
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/7891321
关键词：
Address Affect Age American Bone Morphogenetic Proteins Candidate Disease Gene Cartilage Cells Cephalic Characteristics Chondrocytes Cleft Palate Complex Congenital Abnormality DNA Sequence Rearrangement Defect Deformity Degenerative polyarthritis Development Disease Dissection Elements Embryo Epithelium Erinaceidae Event Exostoses Failure Gene Expression Gene Targeting Genes Genetic Epistasis Genetic Screening Genome Genotype Growth Human Interruption Knowledge Lead Learning Maps Mediating Mesenchyme Methods Morphogenesis Mutation Neural Crest Oral cavity Orthologous Gene Osteoblasts Pain Palate Pathogenesis Pathway interactions Pattern Phase Phenotype Platelet-Derived Growth Factor Population Process Regulator Genes Research Personnel Series Shapes Signal Pathway Signal Transduction Skeletal Development Skeleton Staging Testing Time Tissue Differentiation Zebrafish base bone duplicate genes experience gene function genetic element histogenesis human SMO protein improved insight loss of function mutant oral ectoderm osteoblast differentiation palatogenesis parathyroid hormone-related protein positional cloning progenitor programs receptor skeletal skeletal tissue skeletogenesis stem

项目摘要

Cells that form the skeleton first become patterned into specific shapes, and then differentiate to form stiff, supporting, structural elements. Cleft palate, one of the most common birth defects, arises from disruptions in the patterning phase of skeletogenesis, and osteoarthritis, which will affect nearly one in five Americans during the coming decade, stem from disturbed control of skeletal tissue differentiation and histogenesis. Both disorders can appear with improper functioning of developmental regulatory genes that control reciprocal signaling between cells that govern skeletal development. Our project investigates early developmental stages of zebrafish to understand reciprocal signaling in skeletogenesis. We hypothesize that a pathway patterning the palatal skeleton involves specific interactions among Sonic hedgehog, Platelet- derived growth factor, and other signals. We hypothesize that a pathway controlling histogenesis of cartilage and cartilage-replacement bone involves specific interactions among Bone morphogenetic proteins, Indian hedgehog, and Parathyroid hormone related protein. To test these hypotheses, we will examine the detailed abnormal developmental and skeletal phenotypes that arise by perturbing functions of genes in these pathways. We also propose to carry out forward and reverse genetic screens to identify new skeletal mutants. Our findings will improve our knowledge of signaling pathways between cranial epithelia and mesenchyme, and between cartilage and bone progenitors, and thereby inform our understanding of the pathogenesis of cleft palate and osteoarthritis.

形成骨骼的细胞首先变成特定形状，然后区分形成僵硬，支持的结构元素。 left的口感是最常见的先天缺陷之一，是由中断引起的在骨骼生成和骨关节炎的图案阶段，这将影响近五分之一的美国人在接下来的十年中，源于对骨骼组织分化和组织发生的控制。这两种疾病都可以通过控制性调节基因的不当功能而出现控制骨骼发育的细胞之间的相互信号传导。我们的项目提早调查斑马鱼的发育阶段了解骨骼生成中的相互信号传导。我们假设这一点构成pa骨骨骼的途径涉及声音刺猬，血小板之间的特定相互作用得出的生长因子和其他信号。我们假设一条控制软骨组织发生的途径软骨替代骨涉及骨形态发生蛋白之间的特定相互作用刺猬和甲状旁腺激素相关的蛋白质。为了检验这些假设，我们将研究详细的通过这些基因的扰动功能而产生的异常发育和骨骼表型途径。我们还建议进行前进和反向遗传筛选以识别新的骨骼突变体。我们的发现将提高我们对颅性上皮和信号通路的了解间充质以及软骨和骨祖细胞之间，从而告知我们对 left裂和骨关节炎的发病机理。