Role of Trps1 in endochondral bone formation

Trps1 在软骨内骨形成中的作用

• 批准号: 8260988
• 负责人: Dobrawa Napierala
• 金额: $ 1.33万
• 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 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8260988
• 关键词: Role; Trps1; endochondral; bone; formation

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.

描述（由申请人提供）： 摘要：人类 TRPS1 基因突变导致显性遗传性骨骼发育不良毛鼻指骨综合征 (TRPS)。尽管该基因在几年前就已被识别，但 TRPS 背后的分子和细胞机制在很大程度上尚不清楚。 Trps1 是一种 GATA 型转录因子，充当转录抑制因子。最近，我们已经证明，破坏小鼠体内的Trps1基因会导致生长板显着伸长，并延迟软骨被骨的替代。这些异常伴随着 Indian Hedgehog (Ihh) 表达的增加以及 Ihh 和 BMP 信号传导的增加。尽管 BMP 和 Ihh 通路并行作用，调节软骨内骨形成的各个方面，但尚不清楚它们如何在转录水平上整合和控制。该提议的假设是，Trps1 限制 Ihh-BMP 正反馈回路，以确保软骨细胞成熟的及时进展以及软骨细胞发育与软骨周矿化的同步。我们提出的研究旨在阐明 Trps1 分子网络及其在调节分化软骨细胞和软骨膜之间的串扰中的作用。具体来说，我们将重点了解Trps1突变小鼠中延迟软骨去除和软骨内骨化的机制。为了解决这些问题，我们提出以下具体目标： 1.了解Trps1基因破坏引起生长板伸长的分子和细胞机制。 2. 确定Trps1如何调节BMP和hedgehog信号传导。第一个目标将通过对 TRPS 小鼠模型生长板异常进行组织学和分子分析来实现。为了实现第二个目标，我们将结合使用电泳迁移率变动测定 (EMSA)、报告基因表达测定以及分析软骨形成细胞模型中 Trps1 缺乏和过度表达对 BMP 和刺猬信号传导的影响。此外，我们将使用Trps1;Ihh双突变小鼠测试Trps1和Ihh遗传拮抗作用。拟议研究的结果将明确毛犀指骨综合征骨骼发育不良的分子机制。重要的是，这些研究的结果将直接影响我们对广泛参与多器官系统发育的BMP和hedgehog信号传导转录控制的理解。 公共卫生相关性： 项目叙述该项目的重点是阐明毛犀指骨综合征（TRPS）骨骼异常的分子机制。这项研究的结果将直接影响我们对骨骼发育分子调控的理解。