Defining the Role of Trps1 in Phosphate Mediated Mineralization

定义 Trps1 在磷酸盐介导的矿化中的作用

• 批准号: 9033664
• 负责人: Maria C Kuzynski
• 金额: $ 2.24万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-26 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9033664
• 关键词: Affect; Binding; Binding Sites; Biological Assay; Bone Density; Bone Marrow; Cells; Cytoskeleton; DNA; Data; Dental; Dentin; Disease; Elements; Epidermal Growth Factor; Feedback; Gene Expression; Genes; Genetic study; Hydroxyapatites; In Vitro; Knowledge; Mass Spectrum Analysis; Mediating; Metabolic Diseases; Metabolism; Microarray Analysis; Modification; Molecular; Molecular Abnormality; Mus; Mutate; Mutation; Nerve Growth Factors; Odontoblasts; Patients; Phosphorylation; Population; Process; Proteins; Quantitative Trait Loci; Regulation; Reporter; Reporting; Role; Serine; Signal Pathway; Signal Transduction; Signaling Molecule; Stromal Cells; Syndrome; Transcriptional Activation; Transcriptional Regulation; Transduction Gene; Transgenic Mice; Up-Regulation; base; calcium phosphate; chromatin immunoprecipitation; inorganic phosphate; mineralization; mutant; overexpression; promoter; public health relevance; response; skeletal; transcription factor

 DESCRIPTION (provided by applicant): Mineralization is the process in which crystals of calcium phosphate (hydroxyapatite) are laid down within the extra cellular matrix. The availability of phosphate is one of the critical factors affecting this process. Phosphate regulate mineralization not only as a component of hydroxyapatite crystals, but also as a signaling molecule that induces molecular changes supporting mineralization. It has been demonstrated that mineralizing cells respond to phosphate by activating the Erk1/2 common signal transduction proteins and by changing the expression of mineralization-related genes. It was also identified that promoters of these genes are enriched in GATA elements, suggesting that they are regulated by GATA transcription factors. Numerous studies suggest that Trps1, a GATA-type transcription factor, is involved in the formation of a mineralized matrix. First, mutations in the TRPS1 gene cause tricho-rhino-phalangeal syndrome (TRPS) or Ambras syndrome, both of which display skeletal and dental abnormalities. In addition, our previous studies using mice deficient for or overexpressing Trps1 have indicated a role for Trps1 in mineralization. Furthermore, our in vitro analyses show that Trps1-deficiency in odontoblastic cells results in an inability to initiate mineralization; whereas Trps1- upregulation results in delayed and decreased mineralization. Global gene expression analyses demonstrated that the expression of many mineralization-related genes depends on Trps1. Of these genes, the most dysregulated are those involved in phosphate metabolism, thus suggesting a role for Trps1 in phosphate signaling/regulation. This is further supported by our preliminary data demonstrating altered phosphate- induced Erk1/2 activation in Trps1 -deficient and Trps1-overexpressing cells. Although it is apparent that phosphate is critical for the mineralization process, little is known about the molecular network of this process. By deciphering the role of Trps1 in phosphate-mediated mineralization, we can increase our understanding of how mineralization disorders develop.

 描述（由申请人提供）：矿化是磷酸钙（羟基磷灰石）晶体沉积在细胞外基质中的过程。磷酸盐的有效性是影响该过程的关键因素之一。磷酸盐不仅作为羟基磷灰石晶体的组分调节矿化，而且作为诱导支持矿化的分子变化的信号分子。研究表明，矿化细胞通过激活Erk 1/2共同信号转导蛋白和改变矿化相关基因的表达来响应磷酸盐。这些基因的启动子富含加塔元件，表明它们受加塔转录因子的调控。大量研究表明，Trps 1，GATA型转录因子，参与形成矿化基质。首先，TRPS 1基因的突变会导致鼻-指-趾综合征（TRPS）或Ambras综合征，这两种综合征都表现出骨骼和牙齿异常。此外，我们以前使用缺乏或过度表达Trps 1的小鼠的研究表明Trps 1在矿化中的作用。此外，我们的体外分析表明，成牙本质细胞中的Trps 1缺乏导致无法启动矿化;而Trps 1上调导致矿化延迟和降低。全球基因表达分析表明，许多矿化相关基因的表达依赖于Trps 1。在这些基因中，最失调的是那些参与磷酸盐代谢的基因，从而表明Trps 1在磷酸盐信号传导/调节中的作用。我们的初步数据进一步支持了这一点，表明在Trps 1缺陷和Trps 1过表达细胞中磷酸盐诱导的Erk 1/2活化发生了改变。虽然磷酸盐对矿化过程至关重要，但对这一过程的分子网络知之甚少。通过破译Trps 1在磷酸盐介导的矿化中的作用，我们可以增加我们对矿化障碍如何发展的理解。