Jab1-BMP signaling interaction in chondrocyte differentiation

Jab1-BMP 信号在软骨细胞分化中的相互作用

• 批准号: 9273260
• 负责人: Guang Zhou
• 金额: $ 34.87万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9273260
• 关键词: Abnormal Cell; Acute; Address; Adverse effects; Affect; Apoptosis; Attenuated; BMP2 gene; BMP7 gene; Bone Morphogenetic Proteins; Bone Regeneration; COPS5 gene; Cartilage; Cell Cycle Progression; Cell Differentiation process; ChIP-seq; Chondrocytes; Clinical; Defect; Degenerative Disorder; Degenerative polyarthritis; Development; Developmental Process; Diagnosis; Dose; Dwarfism; Embryo; Embryonic Development; Ensure; Exhibits; Family; Feedback; Fracture; Gap Junctions; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genetic; Genetic Transcription; Goals; Growth; Health system; Histologic; Human; Hypertrophy; Implant; In Situ; Inflammatory; Joint repair; Lead; Malignant Neoplasms; Mediating; Mediation; Modeling; Molecular; Molecular Profiling; Mus; Musculoskeletal; Mutation; Natural regeneration; Neonatal; Osteogenesis; Pain; Patients; Phosphorylation; Physiological; Play; Prevention; Proteins; Publishing; Research; Role; Signal Pathway; Signaling Protein; Skeletal Development; Spinal Fusion; Testing; Transactivation; Trauma; Treatment Efficacy; Work; base; bone healing; cartilage repair; chondrodysplasia; cofactor; cost; dosage; experimental study; gain of function; genetic manipulation; improved; in vivo; inhibitor/antagonist; long bone; loss of function; mutant; mutant mouse model; novel; novel therapeutics; osteogenic; overexpression; parathyroid hormone-related protein; public health relevance; recombinase-mediated cassette exchange; repaired; response; skeletal; skeletal disorder; skeletal dysplasia; skeletogenesis; spatiotemporal; therapeutic target; transcription factor; transcriptome sequencing; whole genome

 DESCRIPTION (provided by applicant): The goal of this project is to understand the interaction of Jab1 and BMP signaling during chondrocyte differentiation. BMP signaling is important for all aspects of cartilage and bone formation, bone healings, and joint and cartilage repair. BMP2- and BMP7-containing osteogenic implants have been used for bone regeneration in over one million patients worldwide in the treatment of long-bone nonunion and acute fracture and in spinal fusion. However, the clinical use of BMPs requires super-physiological doses, resulting in high cost and potential inflammatory side effects. Thus, improving BMP treatment efficacy is critical to ease physical pain and financial burdens on patients, their families, and or health system. Furthermore, mutations in BMP signaling components lead to severe human skeletal developmental defects. We have recently identified transcriptional cofactor Jab1 as a novel inhibitor of BMP signaling downstream effector Smad1/5. Jab1 plays essential roles during various developmental processes by modulating other transcription factors' function. Jab1 is broadly expressed during embryogenesis, including in the chondrocytes. However, the role of Jab1 in cartilage formation remains mostly unknown. In our preliminary study, the loss of Jab1 specifically in chondrocytes using the loxP/Cre system led to neonatal lethal chondrodysplasia in mice, demonstrating that Jab1 is essential for proper cartilage formation in vivo. Furthermore, gene expression profiling and ex vivo culture experiments with Jab1 deficient primary chondrocytes revealed increased expression of Smad1/5 and its downstream targets Ihh and Col10a1. Thus, we hypothesize that Jab1 regulates chondrocyte differentiation by directly repressing Smad1/5-mediated BMP signaling. In this study, we propose three specific aims to test this hypothesis. Aim 1 is to use complementary cellular and molecular approaches to delineate the underlying mechanism of Jab1-BMP signaling interaction in chondrocyte differentiation. Aim 2 is to determine the effect of the genetic manipulation of Jab1 expression (both gain- and loss-of-function), specifically in chondrocytes in an inducible manner, on BMP-mediated embryonic cartilage formation using histological and in situ analysis. Aim 3 is to use RNA-seq and ChIP-seq to investigate the direct Jab1 downstream targets in chondrocytes. Overall, this study will further our understanding of the essential role of Jab1 in BMP-mediated skeletal development and generate novel mutant mouse models for skeletal dysplasia research. Ultimately, new therapies based on controlling the Jab1-mediated inhibition of BMP signaling will open a new era in treating acute fracture, osteoarthritis, and the skeletal disorders associated with dys-regulated BMP signaling.

 描述（由适用提供）：该项目的目的是了解软骨细胞分化过程中JAB1和BMP信号的相互作用。 BMP信号传导对于软骨和骨形成，骨骼愈合以及关节和软骨修复的各个方面都很重要。全球超过100万名患者的骨骼再生用于治疗长骨骨和急性骨折以及脊柱融合。但是，BMP的临床使用需要超级生理剂量，从而导致高成本和潜在的炎症副作用。这对于缓解患者，家人和 /或卫生系统的身体疼痛和金融燃烧至关重要。此外，BMP信号传导成分的突变导致严重的人类骨骼发育缺陷。我们最近将转录辅因子jab1确定为BMP信号下游效应器SMAD1/5的新型抑制剂。 JAB1通过调节其他转录因子的功能，在各种发育过程中扮演重要角色。 JAB1在胚胎发生过程中广泛表达，包括在软骨细胞中。但是，JAB1在软骨形成中的作用仍然是未知的。在我们的初步研究中，使用LOXP/CRE系统在软骨细胞中特别丢失JAB1导致小鼠的新生儿致死性软骨发育症，这表明JAB1对于体内适当的软骨形成至关重要。此外，使用JAB1特异性原发软骨细胞进行基因表达分析和离体培养实验，显示SMAD1/5及其下游靶标IHH和COL10A1的表达增加。这是我们假设JAB1通过直接反映SMAD1/5介导的BMP信号传导来调节软骨细胞的分化。在这项研究中，我们提出了三个特定的目的来检验这一假设。目的1是使用完整的细胞和分子方法来描述软骨细胞分化中JAB1-BMP信号相互作用的基本机制。 AIM 2是确定JAB1表达的遗传操纵（均获得功能丧失和功能丧失）的影响，特别是在软骨细胞中以诱导的方式，对BMP介导的胚胎软骨形成，使用组织学和原位分析。 AIM 3是使用RNA-SEQ和CHIP-SEQ研究软骨细胞中的直接JAB1下游靶标。总体而言，这项研究将进一步了解JAB1在BMP介导的骨骼发育中的基本作用，并为骨骼发育不良研究生成新型的突变小鼠模型。最终，基于控制JAB1介导的BMP信号传导抑制的新疗法将在治疗急性骨折，骨关节炎和与DYS受调节的BMP信号相关的骨骼疾病方面开放一个新时代。