RI COBRE: ENDOCRINE AND NUTRITIONAL CONTROL OF LONG BONE GROWTH

RI COBRE：长骨生长的内分泌和营养控制

• 批准号: 7610822
• 负责人: Chanika Phornphutkul
• 金额: $ 31.43万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7610822
• 关键词: Bone Growth; Cell Size; Cells; Chondrocytes; Chondrogenesis; Computer Retrieval of Information on Scientific Projects Database; Data; Endocrine; Essential Amino Acids; Fetal Growth; Funding; Grant; Growth; Hypertrophy; Institution; Insulin; Insulin-Like Growth Factor I; Leucine; Maintenance; Mediating; Metatarsal bone structure; Modeling; Nutrient; Nutritional; Pathway interactions; Phosphotransferases; Physiological; Rattus; Regulation; Research; Research Personnel; Resources; Role; Signal Transduction; Sirolimus; Somatomedins; Somatotropin; Source; System; Testing; United States National Institutes of Health; Work; articular cartilage; base; deprivation; detection of nutrient; fetal; in vivo; inhibitor/antagonist; long bone; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Linear bone growth and maintenance of articular cartilage both require the proliferation and differentiation of chondrocytes. Much of the work done on chondrogenesis has focused on the role of the growth hormone (GH)/insulin-like growth factor-l (IGF-I) axis. While it has long been known that nutrient deprivation impairs linear growth, this has widely been considered to be a function of indirect nutrient effects through modulation of the GH/IGF-I axis. However, our preliminary data indicate that the essential amino acid leucine can directly modulate chondrogenesis. Given that chondrocyte differentiation involves cellular hypertrophy, and that the recently characterized mammalian Target of Rapamycin (mTOR) pathway regulates cell size in response to nutrient availability, we hypothesized that nutrient signaling via mTOR might exert direct effects on chondrocytes. In preliminary studies, we found that rapamycin, an mTOR inhibitor, blocked differentiation of ATDC5 chondrogenic cells. However, leucine restriction also inhibited differentiation. However, a preliminary examination of the signaling effects of rapamycin versus leucine restriction indicated differences. Similar results in an intact in vivo system, fetal rat metatarsal explants, showed differences between the effects of rapamycin and leucine restriction. Based on these observations, we propose the following aims. Specific Aim 1: We will characterize and compare the induction of chondrocyte differentiation by IGF-I and insulin, focusing on actions mediated through the nutrient-sensing kinase mTOR. Specific Aim 2: We will test the hypothesis that restriction of the availability of essential amino acids has a direct effect on chondrocyte proliferation and differentiation, and that this effect is mediated through effects on mTOR as well as through mTOR-independent mechanisms, which we will characterize. Specific Aim 3: thoughout the course of the studies, the physiological significance of key findings will be assessed through parallel studies using a more physiological model of chondrogenesis and bone growth, fetal rat metatarsal explant cultures. This work has the potential to establish a role for nutrients in the indirect regulation of chondrogenesis via insulin and in direct regulation via the mTOR pathway.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 线性骨生长和关节软骨的维持都需要软骨细胞的增殖和分化。关于软骨形成的大部分工作都集中在生长激素 (GH)/胰岛素样生长因子-1 (IGF-I) 轴的作用上。虽然人们早就知道营养缺乏会损害 线性生长，这被广泛认为是通过调节 GH/IGF-I 轴间接营养效应的函数。然而，我们的初步数据表明必需氨基酸亮氨酸可以直接调节软骨形成。鉴于软骨细胞分化涉及细胞肥大，并且 由于最近鉴定的哺乳动物雷帕霉素靶标 (mTOR) 通路可根据营养可用性调节细胞大小，因此我们假设通过 mTOR 的营养信号传导可能对软骨细胞产生直接影响。在初步研究中，我们发现雷帕霉素（一种 mTOR 抑制剂）可阻断 ATDC5 软骨形成细胞的分化。然而，亮氨酸限制也抑制分化。然而，对雷帕霉素与亮氨酸限制的信号传导作用的初步检查表明存在差异。在完整的体内系统（胎鼠跖骨外植体）中的类似结果显示雷帕霉素和亮氨酸限制的效果之间存在差异。基于这些观察，我们提出以下目标。具体目标 1：我们将描述和比较 IGF-I 和胰岛素对软骨细胞分化的诱导作用，重点关注通过营养感应激酶 mTOR 介导的作用。具体目标 2：我们将检验以下假设：限制必需氨基酸的可用性对 软骨细胞增殖和分化，并且这种效应是通过对 mTOR 的影响以及通过 mTOR 独立机制介导的，我们将对此进行表征。具体目标 3：在整个研究过程中，将通过使用软骨形成和骨生长、胎鼠跖骨外植体培养的更生理学模型的平行研究来评估关键发现的生理意义。这项工作有可能确定营养物质在通过胰岛素间接调节软骨形成和通过 mTOR 途径直接调节中的作用。