Protein Phosphatase Phlpp1 in Cartilage Development & Osteoarthritis Progression

蛋白磷酸酶 Phlpp1 在软骨发育中的作用

基本信息

  • 批准号:
    8687230
  • 负责人:
  • 金额:
    $ 34.98万
  • 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:
    2014-08-15 至 2019-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Osteoarthritis (OA) is the most common form of arthritis, a leading cause of disability in older Americans, and a growing economic burden to our society. Characterized by degradation of articular cartilage, synovitis, subchondral bone thickening, osteophytes, and other joint changes, OA is extremely painful and debilitating. Due to the aging population in the USA, there is an urgent need to provide new solutions that prevent osteoarthritis and/or promote cartilage healing. The experiments outlined in this proposal are designed to validate Phlpp1 as therapeutic target and could be rapidly translated into a therapeutic approach for OA. PHLPP1 (pleckstrin homology domain leucine-rich repeat protein phosphatase, "flip") is an intracellular phosphatase that terminates numerous signaling pathways, including Akt and PKC, to repress proteoglycan and type II collagen synthesis, and affect proliferation, differentiation, and survival. We discovered that PHLPP1 is highly expressed in articular cartilage from osteoarthritis (OA) patients. We hypothesize that PHLPP1 promotes chondrocyte hypertrophy during OA progression by virtue of its ability to regulate Akt and other signaling pathways. The objectives of this project are to define how PHLPP1 contributes to OA progression and skeletal development using both human tissues and animal models and to validate Phlpp1 as a therapeutic target for OA. The specific aims of this project are to: 1) Define the role of Phlpp1 in OA progression by performing DMM surgery on skeletally mature Phlpp1-/- mice and monitoring OA progression through functional testing, imaging and histology. Phlpp inhibitors will also be tested in the DMM model. 2) Determine the role of Phlpp1 in endochondral bone and joint formation by examining bone and cartilage development in Phlpp1-/- animals with microCT imaging, histomorphometry, and in situ hybridization; in vitro differentiation assays with primary chondrocytes, osteoblasts, and osteoclasts from Phlpp1-/- and wildtype mice will also be performed in the presence or absence of Phlpp inhibitors; and 3) Define the epigenetic events and soluble factors controlling PHLPP1 expression in OA cartilage by testing the hypothesis that PHLPP1 expression is epigenetically controlled by DNA demethylation in OA cartilage and/or by inflammation-induced release of Hdac co-repressors. The significance of this work is that PHLPP1 is a new and druggable target whose activities and/or expression could be controlled to reset chondrocyte signaling pathways and slow OA disease progression. The work is innovative because the role of PHLPP1 in cartilage development and disease has never been explored. Our team possesses necessary reagents and expertise and thus is uniquely positioned to efficiently complete this project. Our results will have an impact because they will validate PHLPP1 as therapeutic target and could be rapidly translated into a clinical option for millions of Americans suffering from OA.
描述(由申请人提供):骨关节炎(OA)是最常见的关节炎形式,是美国老年人残疾的主要原因,也是我们社会日益增长的经济负担。骨性关节炎的特点是关节软骨退化、滑膜炎、软骨下骨增厚、骨赘和其他关节变化,骨性关节炎非常痛苦,使人虚弱。由于美国人口老龄化,迫切需要提供新的解决方案来预防骨关节炎和/或促进软骨愈合。本提案中概述的实验旨在验证Phlpp1作为治疗靶点,并可以快速转化为OA的治疗方法。PHLPP1 (pleckstrin同源结构域富含亮氨酸的重复蛋白磷酸酶,“flip”)是一种细胞内磷酸酶,可终止多种信号通路,包括Akt和PKC,抑制蛋白聚糖和II型胶原合成,影响增殖、分化和生存。我们发现PHLPP1在骨关节炎(OA)患者的关节软骨中高度表达。我们假设PHLPP1通过调节Akt和其他信号通路的能力,在OA进展过程中促进软骨细胞肥大。该项目的目标是通过人体组织和动物模型确定PHLPP1如何促进OA进展和骨骼发育,并验证PHLPP1作为OA的治疗靶点。本项目的具体目的是:1)通过对骨骼成熟的Phlpp1-/-小鼠进行DMM手术,通过功能检测、影像学和组织学监测OA进展,明确Phlpp1在OA进展中的作用。Phlpp抑制剂也将在DMM模型中进行测试。2)通过显微ct成像、组织形态学测量和原位杂交检测Phlpp1-/-动物的骨和软骨发育,确定Phlpp1在软骨内骨和关节形成中的作用;Phlpp1-/-和野生型小鼠的原代软骨细胞、成骨细胞和破骨细胞的体外分化实验也将在Phlpp抑制剂存在或不存在的情况下进行;3)通过验证OA软骨中PHLPP1表达受DNA去甲基化和/或炎症诱导的Hdac共抑制因子释放的表观遗传控制的假设,明确OA软骨中控制PHLPP1表达的表观遗传事件和可溶性因子。这项工作的意义在于PHLPP1是一种新的可药物靶点,其活性和/或表达可以通过控制重置软骨细胞信号通路和减缓OA疾病进展。这项工作具有创新性,因为PHLPP1在软骨发育和疾病中的作用从未被探索过。我们的团队拥有必要的试剂和专业知识,因此具有独特的优势,可以有效地完成这个项目。我们的研究结果将产生影响,因为它们将验证PHLPP1作为治疗靶点,并可以迅速转化为数百万患有OA的美国人的临床选择。

项目成果

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Jennifer J Westendorf其他文献

Jennifer J Westendorf的其他文献

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{{ truncateString('Jennifer J Westendorf', 18)}}的其他基金

Phlpp phosphatases in osteoarthritis
骨关节炎中的 Phlpp 磷酸酶
  • 批准号:
    10707868
  • 财政年份:
    2022
  • 资助金额:
    $ 34.98万
  • 项目类别:
Phlpp phosphatases in osteoarthritis
骨关节炎中的 Phlpp 磷酸酶
  • 批准号:
    10318360
  • 财政年份:
    2022
  • 资助金额:
    $ 34.98万
  • 项目类别:
Girk2/3 channels in cartilage biology and disease
Girk2/3 通道在软骨生物学和疾病中的作用
  • 批准号:
    9755834
  • 财政年份:
    2019
  • 资助金额:
    $ 34.98万
  • 项目类别:
Girk2/3 channels in cartilage biology and disease
Girk2/3 通道在软骨生物学和疾病中的作用
  • 批准号:
    9902333
  • 财政年份:
    2019
  • 资助金额:
    $ 34.98万
  • 项目类别:
Protein Phosphatase Phlpp1 in Cartilage Development & Osteoarthritis Progression
蛋白磷酸酶 Phlpp1 在软骨发育中的作用
  • 批准号:
    9316518
  • 财政年份:
    2014
  • 资助金额:
    $ 34.98万
  • 项目类别:
Phlpp protein phosphatases in cartilage development and disease
Phlpp 蛋白磷酸酶在软骨发育和疾病中的作用
  • 批准号:
    10021149
  • 财政年份:
    2014
  • 资助金额:
    $ 34.98万
  • 项目类别:
Runx2 and Axin2 Interactions During Bone Formation
Runx2 和 Axin2 在骨形成过程中的相互作用
  • 批准号:
    8092653
  • 财政年份:
    2010
  • 资助金额:
    $ 34.98万
  • 项目类别:
Runx2 and Axin2 Interactions During Bone Formation
Runx2 和 Axin2 在骨形成过程中的相互作用
  • 批准号:
    8721570
  • 财政年份:
    2010
  • 资助金额:
    $ 34.98万
  • 项目类别:
Runx2 and Axin2 Interactions During Bone Formation
Runx2 和 Axin2 在骨形成过程中的相互作用
  • 批准号:
    8685767
  • 财政年份:
    2010
  • 资助金额:
    $ 34.98万
  • 项目类别:
Runx2 and Axin2 Interactions During Bone Formation
Runx2 和 Axin2 在骨形成过程中的相互作用
  • 批准号:
    8485581
  • 财政年份:
    2010
  • 资助金额:
    $ 34.98万
  • 项目类别:

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