The Role of PGRN Growth Factor in Osteoarthritis

PGRN 生长因子在骨关节炎中的作用

基本信息

  • 批准号:
    8698896
  • 负责人:
  • 金额:
    $ 47.49万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-11-23 至 2015-08-31
  • 项目状态:
    已结题

项目摘要

Osteoarthritis (OA) is a degenerative joint disease that affects more than 46 million people in the United States alone. Since mechanisms by which OA ensues are largely unknown, there are no therapeutic targets that effectively prevent and treat the disease. However, growth factors, cytokines and matrix-degrading enzymes are strongly implicated in initiating and aggravating OA lesions. Thus, a molecular understanding of interplays among these molecules will provide invaluable information toward the search for novel therapeutic targets for OA. Our genome-wide screen for novel, differentially expressed genes in OA led to the isolation of progranulin (PGRN) as a novel OA-associated growth factor. In subsequent global screen for the binding proteins of PGRN, we were surprised to find that PGRN bound to TNF Receptors (TNFR). PGRN directly binds to TNFR2 with an approximately 600-fold higher affinity than TNFα, and PGRN-activated target gene expressions in chondrocytes depend on TNFR2. In addition, PGRN blocks the binding of TNFα to TNFR and inhibits TNFα-induced ADAMTS cleavage of cartilage oligomeric matrix protein (COMP). Deletion of the PGRN gene exacerbates, whereas recombinant PGRN prevents, the spontaneous development of polyarthritis in TNF transgenic mice. This proposal specifically focuses on the hypothesis that PGRN exerts its chondroprotective role in the pathogenesis of OA by interacting with TNFR. The Specific Aims are: (1) what are the molecular mechanisms and signaling pathways by which PGRN regulates chondrocyte metabolism? We will define the effects of PGRN and TNFα on chondrocyte metabolism, their signaling pathways, target gene expressions and interplays in chondrocytes. We will determine the dependence of the PGRN function on TNFR in chondrocytes and characterize the PGRN/TNFR receptor complexes. Normal and arthritic human chondrocytes, as well as wildtype and PGRN-/- murine articular chondrocytes, will be used. (2) Does PGRN play an important role in the initiation and progression of OA, and what are the mechanisms of its action in OA? We will take advantage of both systematic and inducible PGRN knockout mice to generate surgically-induced OA models. We will also determine whether recombinant PGRN protects mice against OA challenge and whether PGRN ameliorates existing OA. We will determine which TNFR is important for mediating PGRN’s protective role in OA. By applying insights from in vitro studies (proposed in Aim1) to the analysis of early and late events in the mouse models, we will gain understanding of the molecular events underlying the initiation and progression of OA. Successful completion of the proposed research will not only benefit our understanding of the molecular mechanisms by which growth factor and cytokine act in concert in chondrocytes and in OA, but may also lead to the development of novel therapeutic intervention strategies for degenerative diseases, including OA.
骨关节炎(OA)是一种退行性关节疾病,在美国有超过4600万人受到影响 独自一人。由于骨性关节炎继发的机制在很大程度上是未知的,目前还没有有效的治疗靶点。 预防和治疗该病。然而,生长因子、细胞因子和基质降解酶 与引发和加重骨性关节炎病变密切相关。因此,对相互作用的分子理解 这些分子将为寻找新的治疗靶点提供宝贵的信息 骨关节炎。我们对骨性关节炎新的差异表达基因的全基因组筛选导致了原颗粒的分离 前列环素(PGRN)是一种新的骨钙素相关生长因子。在随后对PGRN结合蛋白的全局筛选中, 我们惊讶地发现,PGRN与肿瘤坏死因子受体(TNFR)结合。PGRN通过一个 在软骨细胞中的亲和力比肿瘤坏死因子α和pGRN激活的靶基因表达高约600倍 依赖于TNFR2。此外,pGRN还可阻断肿瘤坏死因子α与肿瘤坏死因子受体的结合,并抑制肿瘤坏死因子α诱导 软骨寡聚基质蛋白(COMP)的ADAMTS裂解。PGRN基因的缺失加剧了, 而重组PGRN则可预防肿瘤坏死因子转基因小鼠的多发性关节炎的自发发展。 这一建议特别强调了PGRN在发病机制中发挥软骨保护作用的假设 通过与肿瘤坏死因子受体相互作用,促进骨性关节炎的发生。具体目标是:(1)分子机制是什么 以及PGRN调节软骨细胞代谢的信号通路?我们将定义 前列环素和肿瘤坏死因子α对软骨细胞代谢、信号通路、靶基因表达及相互作用的影响 在软骨细胞中。我们将确定软骨细胞中PGRN功能对TNFR的依赖性和 鉴定PGRN/TNFR受体复合体。正常人和关节炎人软骨细胞,以及野生型 和PGRN-/-小鼠关节软骨细胞。(2)PGRN在启动过程中是否起重要作用 以及它在骨性关节炎中的作用机制是什么?我们将利用 系统性和诱导性的PGRN基因敲除小鼠建立手术诱导的骨性关节炎模型。我们还将 确定重组PGRN是否保护小鼠免受OA攻击,以及PGRN是否改善 现有的办公自动化系统。我们将确定哪种TNFR在介导PGRN在骨关节炎中的保护作用中起重要作用。通过应用 来自体外研究(在Aim1中提出的)对小鼠模型中早期和晚期事件分析的见解, 我们将了解骨性关节炎发生和发展的分子机制。成功 完成这项拟议的研究不仅有助于我们对分子机制的理解 生长因子和细胞因子通过这种方式在软骨细胞和骨关节炎中协同作用,但也可能导致 开发包括骨性关节炎在内的退行性疾病的新的治疗干预策略。

项目成果

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Chuanju Liu其他文献

Chuanju Liu的其他文献

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{{ truncateString('Chuanju Liu', 18)}}的其他基金

Targeting TNF Receptors to Inhibit Inflammation and to Prompt Bone Regeneration in Type 1 Diabetes
靶向 TNF 受体抑制炎症并促进 1 型糖尿病的骨再生
  • 批准号:
    10915157
  • 财政年份:
    2023
  • 资助金额:
    $ 47.49万
  • 项目类别:
The immunological mechanism of PGRNs anti-inflammatory effect
PGRNs抗炎作用的免疫学机制
  • 批准号:
    10912299
  • 财政年份:
    2023
  • 资助金额:
    $ 47.49万
  • 项目类别:
The Role of Sodium Channel Nav1.7 in Osteoarthritis - Resubmission - 1
钠通道 Nav1.7 在骨关节炎中的作用 - 重新提交 - 1
  • 批准号:
    10390155
  • 财政年份:
    2022
  • 资助金额:
    $ 47.49万
  • 项目类别:
A new mouse model to study GBA1 mutation-associated diseases with multiple organs involvement
研究GBA1突变相关多器官疾病的新小鼠模型
  • 批准号:
    10651885
  • 财政年份:
    2022
  • 资助金额:
    $ 47.49万
  • 项目类别:
A new mouse model to study GBA1 mutation-associated diseases with multiple organs involvement
研究GBA1突变相关多器官疾病的新小鼠模型
  • 批准号:
    10508985
  • 财政年份:
    2022
  • 资助金额:
    $ 47.49万
  • 项目类别:
Targeting TNF Receptors to Inhibit Inflammation and to Prompt Bone Regeneration in Type 1 Diabetes - Resubmission - 1
靶向 TNF 受体抑制 1 型糖尿病炎症并促进骨再生 - 重新提交 - 1
  • 批准号:
    10453563
  • 财政年份:
    2020
  • 资助金额:
    $ 47.49万
  • 项目类别:
Targeting TNF Receptors to Inhibit Inflammation and to Prompt Bone Regeneration in Type 1 Diabetes - Resubmission - 1
靶向 TNF 受体抑制 1 型糖尿病炎症并促进骨再生 - 重新提交 - 1
  • 批准号:
    10218061
  • 财政年份:
    2020
  • 资助金额:
    $ 47.49万
  • 项目类别:
Progranulin: A Novel Gene in Gaucher Diseases
颗粒体蛋白前体:戈谢病的一个新基因
  • 批准号:
    10251862
  • 财政年份:
    2017
  • 资助金额:
    $ 47.49万
  • 项目类别:
Progranulin: A Novel Gene in Gaucher Diseases
颗粒体蛋白前体:戈谢病的一个新基因
  • 批准号:
    10011889
  • 财政年份:
    2017
  • 资助金额:
    $ 47.49万
  • 项目类别:
Progranulin Intervention in Inflammatory Bowel Diseases
颗粒体蛋白前体干预炎症性肠病
  • 批准号:
    8708276
  • 财政年份:
    2013
  • 资助金额:
    $ 47.49万
  • 项目类别:

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