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CITED2 and Mechanical Loads

CITED2 和机械载荷

基本信息

批准号：
7893126
负责人：
HUI Bin SUN
金额：
$ 28.1万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-18 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7893126
关键词：
Address Arthritis Binding Biological Biological Assay Biological Process Cartilage Cartilage Matrix Cattle Cell Line Cells Chondrocytes Connective Tissue Degenerative polyarthritis Dependency Dominant-Negative Mutation EP300 gene ETS1 gene Elements Enzymes Excision Family member Gelatinase A Gene Expression Gene Targeting Herb Hydrostatic Pressure Immobilization In Vitro Interstitial Collagenase Joints Link Liquid substance MAP Kinase Gene Matrix Metalloproteinases Measures Mechanics Mediating Messenger RNA Metalloproteinase Gene Molecular Monitor Pathologic Peptides Phosphotransferases Physiological Pilot Projects Production Protein Isoforms Proteins Regulation Regulatory Pathway Reporting Research Personnel Rheumatoid Arthritis Signal Pathway Signal Transduction Small Interfering RNA Synovial Cell Tail Testing The Sun Time Tissues Trans-Activators Transactivation Transfection Two-Hybrid System Techniques base combat enzyme activity gallocatechol improved in vitro Assay in vivo joint loading member mitogen-activated protein kinase p38 new therapeutic target novel overexpression programs protective effect research study response therapeutic target transcription factor

项目摘要

DESCRIPTION (provided by applicant): Cartilage degradation, the hallmark of rheumatoid arthritis and osteoarthritis, is closely linked to the tissue's state of mechanical usage. Cartilage breakdown can be induced by mechanical overuse and exacerbated by disuse; however, mechanical loading at physiologically relevant levels can protect joint tissues from degradation. Yet the cellular mechanisms that mediate both the protective effects of physiological loading and the damaging effects of inappropriate mechanical usage remain unclear. We recently identified a novel transcriptional regulator CITED2 (CBP/p300-lnteracting Transactivator with ED-rich tail 2) that is induced in chondrocytes and other cells by physiologically relevant levels of mechanical loading, and whose expression is inversely correlated with the production of matrix metalloproteinases (MMPs) implicated in cartilage degradation. We therefore hypothesize that CITED2 is a key element of the regulatory pathway that mediates the effects of mechanical loading on cartilage degradation. The proposed studies have three specific aims directed at characterizing this signaling pathway: (1) to determine the relationship between changes in CITED2 expression and the regulation of MMPs in chondrocytes responding to mechanical loading (intermittent hydrostatic pressure); (2) to identify molecular mechanisms by which CITED2 regulates the expression of MMP genes; and (3) to identify specific mechanisms by which mechanical loading regulates the expression of CITED2. In these studies we will experimentally modify the expression or activity of molecular components participating in this signaling pathway and monitor resulting changes in the expression of the appropriate target genes (CITED2, MMPs). We will also characterize interactions between molecular members of these regulatory pathways by in vitro and in vivo binding assays. Finally we will test whether the effects of mechanical loading on MMP expression can be mimicked using a biological regulator that has been found to target a specific molecular component of this novel molecular switching mechanism. The results of these studies will thus identify novel targets for therapeutic approaches to combat joint degenerative diseases, and will improve our understanding of the fundamental biological processes underlying both normal connective tissue turnover and pathologic degradation.

描述（由申请人提供）：类风湿性关节炎和骨关节炎的标志性特征是软骨降解，与组织的机械使用状态密切相关。机械过度使用可导致软骨分解，废用可加剧软骨分解;然而，生理相关水平的机械负荷可保护关节组织免受降解。然而，介导生理负荷的保护作用和不适当的机械使用的破坏作用的细胞机制仍然不清楚。我们最近确定了一种新的转录调节因子CITED 2（CBP/p300-交互式反式激活因子与ED丰富的尾巴2），诱导软骨细胞和其他细胞的生理相关水平的机械负荷，其表达呈负相关的生产基质金属蛋白酶（MMPs）参与软骨降解。因此，我们假设CITED 2是调节机械负荷对软骨降解影响的调节途径的关键元件。本研究的目的有三：（1）确定机械负荷下软骨细胞中CITED 2表达变化与MMPs调控之间的关系（2）鉴定CITED 2调节MMP基因表达的分子机制;以及（3）鉴定机械负荷调节CITED 2表达的具体机制。在这些研究中，我们将通过实验改变参与该信号传导途径的分子组分的表达或活性，并监测相应靶基因（CITED 2，MMPs）表达的变化。我们还将通过体外和体内结合试验来表征这些调控途径的分子成员之间的相互作用。最后，我们将测试是否可以使用生物调节剂，已被发现针对这种新的分子开关机制的特定分子组分模拟机械负荷对MMP表达的影响。因此，这些研究的结果将确定新的治疗方法，以打击关节退行性疾病的目标，并将提高我们对正常结缔组织周转和病理性退化的基本生物学过程的理解。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Curcumin slows osteoarthritis progression and relieves osteoarthritis-associated pain symptoms in a post-traumatic osteoarthritis mouse model.

DOI：
10.1186/s13075-016-1025-y
发表时间：
2016-06-03
期刊：
Arthritis research & therapy
影响因子：
4.9
作者：
Zhang Z;Leong DJ;Xu L;He Z;Wang A;Navati M;Kim SJ;Hirsh DM;Hardin JA;Cobelli NJ;Friedman JM;Sun HB
通讯作者：
Sun HB

Green tea polyphenol treatment is chondroprotective, anti-inflammatory and palliative in a mouse post-traumatic osteoarthritis model.

DOI：
10.1186/s13075-014-0508-y
发表时间：
2014-12-17
期刊：
Arthritis research & therapy
影响因子：
4.9
作者：
Leong DJ;Choudhury M;Hanstein R;Hirsh DM;Kim SJ;Majeska RJ;Schaffler MB;Hardin JA;Spray DC;Goldring MB;Cobelli NJ;Sun HB
通讯作者：
Sun HB

Nutraceuticals: potential for chondroprotection and molecular targeting of osteoarthritis.