Role of Trps1 in Endochondral Bone Formation

Trps1 在软骨内骨形成中的作用

• 批准号: 8262423
• 负责人: Dobrawa Napierala
• 金额: $ 7.04万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-10 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8262423
• 关键词: Address; Affect; Antibodies; Apoptosis; Binding; Binding Sites; Biological Assay; Blood Vessels; Cartilage; Cell Line; Cell model; Cells; Chondrocytes; Chondrogenesis; Cleaved cell; Code; Complex; Data; Development; Electrophoretic Mobility Shift Assay; Embryo; Epiphysial cartilage; Erinaceidae; Event; Excision; Feedback; Gene Expression; Gene Targeting; Genes; Genetic; Genetic Recombination; Genetic Transcription; Goals; Histological Techniques; Human; Human Genetics; Immunohistochemistry; In Situ Hybridization; In Vitro; Indium; Inherited; Laboratories; Mediating; Messenger RNA; Methods; Molecular; Molecular Abnormality; Mus; Mutant Strains Mice; Mutation; Nuclear Protein; Osteoclasts; Osteogenesis; Pathogenesis; Pathway interactions; Pattern; Phenotype; Process; Proteins; RNA; RNAi vector; Recombinants; Regulation; Relative (related person); Reporter; Repression; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Skeletal Development; Sonic hedgehog protein; Staging; Staining method; Stains; Syndrome; TdT-Mediated dUTP Nick End Labeling Assay; Testing; Time; Transcription Repressor/Corepressor; Transcriptional Regulation; Transposase; Vascularization; Western Blotting; body system; bone; bone morphogenetic protein 2; cartilage development; caspase-3; cell type; chromatin immunoprecipitation; genetic analysis; in vivo; long bone; malformation; mineralization; mouse model; mutant; parathyroid hormone-related protein; programs; promoter; public health relevance; research study; response; rib bone structure; skeletal; skeletal abnormality; skeletal dysplasia; smoothened signaling pathway; stable cell line; transcription factor

DESCRIPTION (provided by applicant): ABSTRACT Mutations of the human TRPS1 gene cause a dominantly inherited skeletal dysplasia tricho-rhino-phalangeal syndrome (TRPS). Although the gene was identified several years ago, the molecular and cellular mechanisms underlying TRPS are largely unknown. Trps1 is a GATA-type transcription factor that acts as a transcriptional repressor. Recently, we have demonstrated that disruption of the Trps1 gene in mice results in dramatic elongation of growth plates and delayed replacement of cartilage by bone. These abnormalities are accompanied by increased Indian hedgehog (Ihh) expression and elevated Ihh and BMP signaling. Although BMP and Ihh pathways act in parallel to regulate various aspects of endochondral bone formation, it is unclear how they are integrated and controlled at the transcriptional level. The hypothesis of this proposal is that Trps1 constrains the Ihh-BMP positive feedback loop to assure timely progression of chondrocyte maturation and synchronization of chondrocyte development with perichondrial mineralization. We propose studies aimed at elucidating the Trps1 molecular network and its role in regulation of the cross-talk between differentiating chondrocytes and perichondrium. Specifically, we will focus on understanding the mechanisms of delayed cartilage removal and endochondral ossification in Trps1 mutant mice. To address these questions we propose the following specific aims: 1. To understand the molecular and cellular mechanisms of the growth plate elongation caused by disruption of the Trps1 gene. 2. To determine how Trps1 regulates BMP and hedgehog signaling. The first aim will be accomplished by histological and molecular analyses of abnormalities in the growth plate of the mouse model of TRPS. To achieve the second aim we will employ a combination of electrophoretic mobility shift assay (EMSA), reporter expression assays and analyses of the effect of the Trps1 deficiency and over-expression on BMP and hedgehog signaling in a cellular model of chondrogenesis. Additionally, we will test the Trps1 and Ihh genetic antagonism using Trps1;Ihh double mutant mice. Results of the proposed studies will define molecular mechanisms underlying skeletal dysplasia in tricho-rhino-phalangeal syndrome. Importantly, the results of these studies will directly impact our understanding of the transcriptional control of BMP and hedgehog signaling, that are widely involved in the development of multiple organ systems. PUBLIC HEALTH RELEVANCE: Project Narrative This project is focused on elucidating the molecular mechanisms of skeletal abnormalities in tricho-rhino-phalangeal syndrome (TRPS). The results of this study will directly impact our understanding of molecular regulation of skeletal development.

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