Effect of NFATs on Chondrocytes

NFAT 对软骨细胞的影响

• 批准号: 6770216
• 负责人: MICHAEL C. NASKI
• 金额: $ 30.88万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6770216
• 关键词: bone morphogenetic proteins; calcineurin; cartilage development; cell differentiation; chondrocytes; developmental genetics; genetic transcription; genetically modified animals; laboratory mouse; normal ossification; protein kinase; transcription factor

DESCRIPTION (provided by applicant): Chondrogenesis is a process of ordered and synchronous differentiation of mesenchymal cells into chondrocytes. Endochondral ossification is a process of chondrocyte differentiation that determines skeletal growth. Our goal is to better understand the signaling and transcriptional pathways that control (i) commitment of mesenchymal cells to the chondrocyte cell lineage and (ii) the differentiation of chondrocytes during endochondral ossification. In the pursuit of this goal, we have identified a novel pathway that induces chondrogenesis and chondrocyte gene expression. In this pathway, elevation of intracellular calcium causes sequential activation of (i) calcineurin and (ii) the transcription factor, nuclear factor of activated T-cell 4 (NFAT4). NFAT4 then enters the nucleus and directly induces BMP-2 gene expression. In turn, BMP-2 acts as an autocrine/paracrine inducer of differentiation. Because calcium-dependent signaling is induced by many growth factors/hormones and basic cell biological processes, we hypothesize that calcium-dependent activation of NFATs and induction of BMP expression is a central pathway regulating chondrogenesis and chondrocyte differentiation. To test this hypothesis and further our understanding of chondrocyte differentiation we will pursue the following Specific Aims: (1) determine the effects of NFAT1, 2, and 3 on chondrogenesis and BMP expression, (2) elucidate the effect of calcineurin and NFAT4 on chondrogenesis and chondrocyte differentiation in vivo, (3) investigate the kinase control of NFATs during chondrogenesis/chondrocyte gene expression, and (4) analyze the transcriptional control of the BMP-2 gene by NFATs and cooperating regulators of transcription. These studies will utilize many reagents created during our preliminary studies and will fundamentally advance our understanding of chondrogenesis and chondrocyte differentiation. We anticipate that these studies will suggest novel ways to promote cartilage regeneration or suppress cartilage degeneration.

描述（由申请人提供）：软骨发生是将间充质细胞分化为软骨细胞的有序和同步分化的过程。内软骨骨化是一个决定骨骼生长的软骨细胞分化过程。我们的目标是更好地了解控制间充质细胞对软骨细胞谱系（i）的信号传导和转录途径，以及（ii）内侧软骨骨化过程中软骨细胞的分化。为了实现这一目标，我们确定了一种新的途径，该途径诱导软骨生成和软骨细胞基因表达。在此途径中，细胞内钙的升高导致（i）钙调神经磷酸酶和（ii）转录因子，激活T细胞4的核因子（NFAT4）的顺序激活。然后NFAT4进入核并直接诱导BMP-2基因表达。反过来，BMP-2充当分化的自分泌/旁分泌诱导剂。由于钙依赖性信号传导是由许多生长因子/激素和基本细胞生物学过程诱导的，因此我们假设钙依赖性NFAT的激活和BMP表达的诱导是调节软骨生成和软骨细胞分化的中心途径。为了检验这一假设并进一步我们对软骨细胞分化的理解，我们将追求以下具体目的：（1）确定NFAT1、2和3对软骨生成和BMP表达的影响，（2）阐明钙调神经磷酸酶和NFAT4对软骨和软骨细胞差异的影响（3）研究在（3）研究中（3）研究KINFO，（3）研究。软骨生成/软骨细胞基因表达和（4）通过NFAT和转录合作调节剂分析BMP-2基因的转录对照。这些研究将利用我们在初步研究中创建的许多试剂，并从根本上促进我们对软骨生成和软骨细胞分化的理解。我们预计这些研究将提出促进软骨再生或抑制软骨变性的新方法。