Transcription Factor NFAT1 Deficiency and Osteoarthritis

转录因子 NFAT1 缺乏与骨关节炎

基本信息

批准号：
8041800
负责人：
JINXI WANG
金额：
$ 33.75万
依托单位：
UNIVERSITY OF KANSAS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-07-11 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8041800
关键词：
Adult Affect Age Aging Antibodies Binding Binding Sites Biological Biological Assay Biological Factors Bone Marrow Cartilage Cell Differentiation process Cell physiology Cells Chondrocytes Chromatin Chronic Complementary DNA Crossbreeding DNA Binding Domain DNA Methylation Data Degenerative polyarthritis Development Disease Progression Electrophoretic Mobility Shift Assay Epigenetic Process Exhibits Functional disorder Gene Expression Gene Targeting Genetic Genetic Predisposition to Disease Goals Histopathology Human Immunohistochemistry Joints Laser Scanning Cytometry Lead Maintenance Mechanics Mesenchymal Stem Cells Molecular Molecular Target Mus Mutation Older Population Osteoarthrosis Deformans Pathogenesis Patients Peptide Hydrolases Phenotype Physiological Prevention strategy Preventive Proteins Research Risk Factors Skeletal Development Stem cells Stromal Cells Structure Synovial Cell Synovial Membrane Testing Therapeutic Tissues Transgenic Mice Weight-Bearing state age related arthropathies articular cartilage base bone cell type chromatin immunoprecipitation cytokine disability histone modification improved innovation insight joint injury mature animal member middle age mouse model novel nuclear factors of activated T-cells overexpression prevent promoter proteinase In transcription factor

项目摘要

DESCRIPTION (provided by applicant): Osteoarthritis (OA) is the most common form of joint disease and the major cause of chronic disability in middle-aged and older populations. Although multiple risk factors, including mechanical abnormalities, aging, joint injuries, and genetic predisposition, have been proposed to be involved in the pathogenesis of OA, no proven structure-modifying pharmacologic therapy is currently available to prevent the initiation of OA or reverse the progression of the disease. Overexpression of catabolic cartilage-degrading proteinases and proinflammatory cytokines has been shown to cause articular cartilage degradation. However, key upstream biological factors that regulate the expression of these catabolic molecules remain unclear. We have recently found that mice lacking Nfat1, a member of the nuclear factor of activated T-cells (NFAT) transcription factors, exhibit normal skeletal development but display OA-like changes with overexpression of catabolic proteinases and cytokines in affected articular cartilage of adult animals. The molecular mechanisms for NFAT1 deficiency- associated OA remain unclear. The objective of this application is to explore the molecular and cellular mechanisms underlying the pathogenesis of Nfat1 deficiency-induced OA in mice. Our central hypothesis is that NFAT1 is a key factor for maintenance of the function of adult articular chondrocytes and mesenchymal progenitor cells in the joint tissues, and that NFAT1 deficiency causes OA through dysfunction of adult articular chondrocytes and pathological differentiation of progenitor cells in the joint. This hypothesis will be tested through the following specific aims: (1) investigate the mechanisms of age-dependent OA phenotype in Nfat1- deficient mice, (2) determine Nfat1 target genes in joint tissue cells, and (3) determine which joint tissue(s) is primarily affected by NFAT1 deficiency. Successful completion of these proposed studies may direct us to develop innovative and effective strategies for the prevention and treatment of OA. PUBLIC HEALTH RELEVANCE: The major goal of this project is to explore the molecular and cellular mechanisms by which transcription factor NFAT1 deficiency causes osteoarthritic joint degeneration. Successful completion of the proposed studies may provide new insights into the etiopathogenesis of osteoarthritis and could lead to improved strategies for prevention and treatment of osteoarthritis.

描述（由申请人提供）：骨关节炎（OA）是中年和较老的慢性残疾的最常见形式，也是慢性残疾的主要原因。尽管已经提议多种危险因素，包括机械异常，衰老，关节损伤和遗传易感性，与OA的发病机理有关，但目前尚无证实的结构修饰药理疗法，以防止OA的启动或逆转疾病的进展。已经证明，分解代谢软骨降解蛋白酶和促炎细胞因子的过表达可引起关节软骨降解。但是，调节这些分解代谢分子表达的关键上游生物学因素尚不清楚。我们最近发现，缺乏活化T细胞（NFAT）转录因子的NFAT1的小鼠表现出正常的骨骼发育，但在受影响的成年动物关节软骨中的分解代谢蛋白酶和细胞因子的过表达显示出OA样变化。 NFAT1缺乏 - 与OA相关的分子机制尚不清楚。该应用的目的是探索小鼠NFAT1缺乏诱导的OA发病机理的基础的分子和细胞机制。我们的中心假设是，NFAT1是维持关节组织中成人关节软骨细胞和间质祖细胞功能的关键因素，而NFAT1缺乏会导致OA通过成人关节软骨细胞的功能障碍和关节中递观细胞的病理学分化的功能障碍。该假设将通过以下特定目的进行检验：（1）研究NFAT1缺陷小鼠中年龄依赖性OA表型的机制，（2）确定关节组织细胞中的NFAT1靶基因，（3）确定哪个关节组织主要受NFAT1缺乏症的影响。这些拟议的研究成功完成可能会指导我们制定创新有效的策略，以预防和治疗OA。公共卫生相关性：该项目的主要目标是探索转录因子NFAT1缺乏引起骨关节炎关节变性的分子和细胞机制。成功完成拟议的研究可能会为骨关节炎的病情发生提供新的见解，并可能导致改进的预防和治疗骨关节炎的策略。