Regulation of limb synovial joint organization and function

肢体滑膜关节组织和功能的调节

基本信息

  • 批准号:
    10508521
  • 负责人:
  • 金额:
    $ 23.23万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-08-01 至 2024-07-31
  • 项目状态:
    已结题

项目摘要

The synovial joints are critical for skeletal motion and function, and their structure, organization, distinct tissues and susceptibility to diseases, including osteoarthritis, are well understood. However, basic aspects of their developmental biology remain unclear. If available, such information and insights could be used to create new joint tissue repair strategies. In early fetal limbs, the skeletal primordia are initially continuous and uninterrupted by joints. Joint development starts with emergence at each prescribed anatomical site of mesenchymal cells, called the interzone, that are dense and compacted and express growth-and- differentiation-factor 5 (Gdf5). Cell lineage tracing and tracking in transgenic mice showed that the Gdf5 expressing cells and progenies represent unique stem cells and produce most, if not all, joint tissues over time, including articular cartilage, ligaments and synovial lining. Though new and broadly relevant, these and other studies left much unclear. Notably, one of the least understood processes in joint formation is how the synovial cavity forms, how it can be created within the compacted interzone and what mechanisms attract and accrue its fluid, surprising gaps in knowledge given the cavity’s critical nature and essential roles. Previous studies showed that joint cavitation is associated with local hyaluronate production, protease expression and muscle motion, all processes contributing to interzone cell-cell contact relaxation. But how does the cavity itself form and enlarge? In preliminary studies, we have found that cavity enlargement requires active and energy- requiring mechanisms able to attract fluid and distance the opposing articulating surfaces from each other, eliciting a synovial cavity space. Using pharmacological approaches, we have found that these mechanisms and their activities are in fact required for cavity formation and growth. These and other preliminary data lead to the central hypothesis that cavitation is a stepwise process brought about by convergence and coordination of distinct regulatory mechanisms. We propose two interrelated Aims in which we will carry out single cell analyses to delineate genes involved and upstream regulatory mechanisms (Aim 1) and will test the roles of these mechanisms in postnatal joint maintenance, endurance and structural and functional capacities (Aim 2). We will make use of diverse analytical approaches including molecular genetics; histomorphometry; microCT; single cell RNAseq; in situ hybridization; tissue isolation; cell cultures and cell fractionation; and imaging quantification and reconstruction. This high risk-high return R21 project is expected to provide wholly novel and previously unsuspected data and insights into joint cavitation and function. Limb joints are affected by various diseases for which current treatments are only partially effective and not long-lasting. With its novel concepts and data, the present project promises to pave the way for the creation of more effective and enduring strategies for joint disease therapy.
滑膜关节是骨骼运动和功能的关键,它们的结构、组织和特点 组织和对包括骨关节炎在内的疾病的易感性是众所周知的。然而,基本的方面 它们的发育生物学尚不清楚。如果有的话,这样的信息和见解可以用来创造 新的关节组织修复策略。在早期胎儿四肢中,骨骼原基最初是连续的, 不被关节打断的。关节发育始于每个指定解剖部位的出现 间充质细胞,称为间带,密度高,致密,表达生长和- 分化因子5(Gdf5)。转基因小鼠的细胞谱系追踪和追踪表明,Gdf5 表达的细胞和后代代表着独特的干细胞,随着时间的推移,即使不是全部,也会产生大部分关节组织, 包括关节软骨、韧带和滑膜衬里。虽然是新的和广泛相关的,但这些和其他 研究留下了很多不清楚的地方。值得注意的是,关节形成中最不了解的过程之一是滑膜是如何形成的 空洞的形成,它是如何在致密的区域内产生的,以及什么机制吸引和积累它的 鉴于洞穴的关键性质和重要作用,在知识方面存在着令人惊讶的流动性差距。以前的研究 研究表明,关节空洞与局部透明质酸的产生、蛋白酶的表达和肌肉有关 运动,所有过程都有助于区间细胞-细胞接触松弛。但是空洞本身是如何形成的呢? 然后放大?在初步研究中,我们发现空洞扩大需要积极和能量- 需要能够吸引流体并使相对的关节表面彼此分开的机构, 形成滑膜腔空间。利用药理学方法,我们发现这些机制和 事实上,它们的活动是空洞形成和生长所必需的。这些和其他初步数据导致 认为空化是一个逐步过程的中心假说是由以下因素引起的 不同的监管机制。我们提出了两个相互关联的目标,在这两个目标中,我们将实现单细胞 分析所涉及的基因和上游调控机制(目标1),并将测试 这些机制涉及出生后的联合维持、耐力以及结构和功能能力(目标2)。 我们将使用多种分析方法,包括分子遗传学;组织形态计量学;显微CT; 单细胞RNAseq;原位杂交;组织分离;细胞培养和细胞分离;以及成像 量化和重建。这个高风险、高回报的R21项目预计将提供全新的 以及对关节空化和功能的先前意想不到的数据和见解。肢体关节受以下因素影响 目前的治疗方法只对部分有效且不能持久的各种疾病。用它的小说 概念和数据,本项目有望为创建更有效和更持久的 关节疾病治疗策略。

项目成果

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Maurizio Pacifici其他文献

Maurizio Pacifici的其他文献

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{{ truncateString('Maurizio Pacifici', 18)}}的其他基金

Regulation of limb synovial joint organization and function
肢体滑膜关节组织和功能的调节
  • 批准号:
    10674028
  • 财政年份:
    2022
  • 资助金额:
    $ 23.23万
  • 项目类别:
Mechanisms regulating normal and ectopic endochondral ossification
正常和异位软骨内骨化的调节机制
  • 批准号:
    9900719
  • 财政年份:
    2017
  • 资助金额:
    $ 23.23万
  • 项目类别:
2016 Bones & Teeth Gordon Research Conference and Gordon Research Seminar
2016 骨头
  • 批准号:
    9204947
  • 财政年份:
    2015
  • 资助金额:
    $ 23.23万
  • 项目类别:
2016 Bones & Teeth Gordon Research Conference and Gordon Research Seminar
2016 骨头
  • 批准号:
    9045147
  • 财政年份:
    2015
  • 资助金额:
    $ 23.23万
  • 项目类别:
Fourth International MHE Research Conference
第四届国际MHE研究会议
  • 批准号:
    8399406
  • 财政年份:
    2012
  • 资助金额:
    $ 23.23万
  • 项目类别:
Pathogenic Mechanisms in Hereditary Multiple Exostoses Syndrome
遗传性多发性外生骨疣综合征的发病机制
  • 批准号:
    10442054
  • 财政年份:
    2011
  • 资助金额:
    $ 23.23万
  • 项目类别:
Pathogenic Mechanisms in Hereditary Multiple Exostoses Syndrome
遗传性多发性外生骨疣综合征的发病机制
  • 批准号:
    10598638
  • 财政年份:
    2011
  • 资助金额:
    $ 23.23万
  • 项目类别:
Pathogenic Mechanisms in Hereditary Multiple Exostoses Syndrome
遗传性多发性外生骨疣综合征的发病机制
  • 批准号:
    9309201
  • 财政年份:
    2011
  • 资助金额:
    $ 23.23万
  • 项目类别:
Mechanisms of Synovial Joint Formation
滑膜关节形成机制
  • 批准号:
    7413662
  • 财政年份:
    2005
  • 资助金额:
    $ 23.23万
  • 项目类别:
Mechanisms of Synovial Joint Formation
滑膜关节形成机制
  • 批准号:
    7235656
  • 财政年份:
    2005
  • 资助金额:
    $ 23.23万
  • 项目类别:
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