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Jab1-BMP signaling interaction in chondrocyte differentiation

Jab1-BMP 信号在软骨细胞分化中的相互作用

基本信息

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
项目类别：
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

项目摘要

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.