Transgene enhancement of hyaluronan in human osteoarthritic cartilage

透明质酸在人骨关节炎软骨中的转基因增强

基本信息

  • 批准号:
    8907905
  • 负责人:
  • 金额:
    $ 16.23万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-08-07 至 2017-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): A key event in the progression of osteoarthritis (OA) is the loss of proteoglycan aggregate from the extracellular matrix of articular cartilage. In addition to aggrecan, a significant decrease in hyaluronan (HA), the core filament of the cartilage proteoglycan aggregate, is also observed in cartilage derived from OA patients as compared to normal human cartilage. These losses are due to changes in the metabolic state of resident chondrocytes. In past studies we have tested the hypothesis that HA turnover occurs primarily through an endocytosis event, mediated by the HA receptor CD44. Experimental conditions that upregulate the loss of aggrecan and HA, also affect an enhancement in CD44 expression and a coordinate increase in HA endocytosis. In addition we have tested whether chondrocytes also use CD44 to "sense" and respond to a loss of proteoglycan by initiating signaling cascades. Until recently we have only been able to examine CD44 functions by using chondrocyte cell-culture studies. The central hypothesis of this new proposal is that HA within the extracellular matrix (ECM) of damaged cartilage is limiting. As such, matrix repair and aggrecan retention are ineffective. We have been recently successful at introducing human transgenes into intact human, bovine and mouse cartilage explants through the use of human adenoviral and adeno-associated virus constructs. This proposal includes several innovative approaches. We will use a gene transfer approach to introduce a HA synthase (HAS2) transgene into intact human OA cartilage explants. This approach will generate a selective and substantial increase in HA within the ECM to address the question of whether an increased deposition of locally-synthesized HA in situ provides for cartilage repair and a diminution of aggrecanolysis biomarkers as resident chondrocytes are coaxed into a state of quiescence. Our second goal will be to determine the mechanism for the HA-induced return to homeostasis and whether HA receptors such as CD44 are responsible. Our long-term goal is to determine the importance of HA to cartilage homeostasis and, how to alter HA metabolism in vivo especially within human articular cartilage.
描述(由申请人提供):骨关节炎(OA)进展中的一个关键事件是关节软骨细胞外基质中蛋白聚糖聚集体的丢失。除了聚集蛋白聚糖之外,与正常人软骨相比,在源自OA患者的软骨中也观察到透明质酸(HA)(软骨蛋白聚糖聚集体的核心细丝)的显著减少。这些损失是由于常驻软骨细胞代谢状态的变化。在过去的研究中,我们已经测试了HA周转主要通过HA受体CD44介导的内吞作用事件发生的假设。上调聚集蛋白聚糖和HA损失的实验条件也影响CD44表达的增强和HA内吞作用的协同增加。此外,我们还测试了软骨细胞是否也使用CD44来“感知”并通过启动信号级联反应蛋白聚糖的损失。直到最近,我们只能通过软骨细胞培养研究来检测CD44的功能。这个新提议的中心假设是受损软骨的细胞外基质(ECM)内的HA是有限的。因此,基质修复和聚集蛋白聚糖保留无效。我们最近已经成功地通过使用人腺病毒和腺相关病毒构建体将人转基因引入完整的人、牛和小鼠软骨外植体中。这项建议包括若干创新办法。我们将使用基因转移方法将HA合酶(HAS 2)转基因导入完整的人OA软骨外植体。这种方法将在ECM内产生HA的选择性和实质性增加,以解决以下问题:当驻留的软骨细胞被诱导进入静止状态时,局部合成的HA原位沉积的增加是否提供软骨修复和聚集蛋白聚糖分解生物标志物的减少。我们的第二个目标将是确定HA诱导恢复稳态的机制,以及HA受体如CD44是否起作用。我们的长期目标是确定HA对软骨稳态的重要性,以及如何改变体内尤其是人关节软骨中HA的代谢。

项目成果

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Warren Knudson其他文献

Warren Knudson的其他文献

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{{ truncateString('Warren Knudson', 18)}}的其他基金

Transgene enhancement of hyaluronan in human osteoarthritic cartilage
透明质酸在人骨关节炎软骨中的转基因增强
  • 批准号:
    8748265
  • 财政年份:
    2014
  • 资助金额:
    $ 16.23万
  • 项目类别:
MATRIX ASSEMBLY BY ARTICULAR CARTILAGE
通过关节软骨进行基质组装
  • 批准号:
    6235737
  • 财政年份:
    1997
  • 资助金额:
    $ 16.23万
  • 项目类别:
CD44 MEDIATED CATABOLISM OF HYALURONAN BY CHONDROCYTES
CD44 介导软骨细胞对透明质酸的分解代谢
  • 批准号:
    2769611
  • 财政年份:
    1996
  • 资助金额:
    $ 16.23万
  • 项目类别:
CD44 MEDIATED CATABOLISM OF HYALURONAN BY CHONDROCYTES
CD44 介导软骨细胞对透明质酸的分解代谢
  • 批准号:
    2517487
  • 财政年份:
    1996
  • 资助金额:
    $ 16.23万
  • 项目类别:
CD44 MEDIATED CATABOLISM OF HYALURONAN BY CHONDROCYTES
CD44 介导软骨细胞对透明质酸的分解代谢
  • 批准号:
    7280952
  • 财政年份:
    1996
  • 资助金额:
    $ 16.23万
  • 项目类别:
CD44 MEDIATED CATABOLISM OF HYALURONAN BY CHONDROCYTES
CD44 介导软骨细胞对透明质酸的分解代谢
  • 批准号:
    6989309
  • 财政年份:
    1996
  • 资助金额:
    $ 16.23万
  • 项目类别:
CD44 MEDIATED CATABOLISM OF HYALURONAN BY CHONDROCYTES
CD44 介导软骨细胞对透明质酸的分解代谢
  • 批准号:
    6375011
  • 财政年份:
    1996
  • 资助金额:
    $ 16.23万
  • 项目类别:
CD44 MEDIATED CATABOLISM OF HYALURONAN BY CHONDROCYTES
CD44 介导软骨细胞对透明质酸的分解代谢
  • 批准号:
    2006445
  • 财政年份:
    1996
  • 资助金额:
    $ 16.23万
  • 项目类别:
CD44 MEDIATED CATABOLISM OF HYALURONAN BY CHONDROCYTES
CD44 介导软骨细胞对透明质酸的分解代谢
  • 批准号:
    6055606
  • 财政年份:
    1996
  • 资助金额:
    $ 16.23万
  • 项目类别:
CD44 MEDIATED CATABOLISM OF HYALURONAN BY CHONDROCYTES
CD44 介导软骨细胞对透明质酸的分解代谢
  • 批准号:
    7119261
  • 财政年份:
    1996
  • 资助金额:
    $ 16.23万
  • 项目类别:

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