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Delineating molecular mechanism of developmental defects of TAR syndrome

描绘 TAR 综合征发育缺陷的分子机制

基本信息

批准号：
10818067
负责人：
Yingwei Mao
金额：
$ 41.19万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-15 至 2025-09-14
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10818067
关键词：
Ablation Affect Anatomy Animal Model Animals Behavioral Binding Bone Development Bone Tissue Cells Cephalic Childhood Cleft Palate Complex Congenital Abnormality Craniofacial Abnormalities Defect Deformity Development Disease Drug Screening Exhibits Exons Face Forehead Forelimb Future Gene Delivery Genes Genetic Research Genetic Risk Genetic study Goals Growth Hand Human Immunoprecipitation Intellectual functioning disability Jaw Knockout Mice Link Mediating Medical Mesenchyme Messenger RNA Methods Mission Molecular Mus Mutation Nature Onset of illness Operative Surgical Procedures Patients Persons Phenotype Platelet Count measurement Population Prevention strategy Process Publishing RNA RNA-Binding Proteins Radial Rare Diseases Regulation Research Role Skeletal Development Structural defect Supportive care Symptoms Syndrome Testing Therapeutic Thrombocytopenia Tissues Viral Viral Genes X-Ray Computed Tomography bone causal variant cell type comorbidity conditional knockout craniofacial craniofacial development design developmental disease effective therapy effectiveness evaluation evidence base fascinate fetal fetus cell functional outcomes gene therapy in utero innovation insight microCT mouse model neurodevelopment new therapeutic target novel novel therapeutic intervention personalized medicine postnatal pre-clinical therapy prevent progenitor restoration risk variant skeletal skeletal disorder stem cells tool transcriptome sequencing

项目摘要

Project Summary Birth defects involving skeletal and craniofacial development are among the most common human congenital diseases with unmet medical needs. Recent genetics studies have identified multiple robust and replicable risk loci to be associated with these devastating anomalies, offering new hope for those afflicted. Among them is the discovery that mutations in RBM8A cause a rare disease called thrombocytopenia-absent- radius (TAR) syndrome. RBM8A gene encodes a RNA-binding protein, yet the precise mechanism by which RBM8A deficiency causes tissue-specific abnormalities remains covered in mystery. In particular, the role of RBM8A deficiency in skeletal dysmorphogenesis and its direct targets in bone development are still unknown. Thus, there is a critical need to elucidate the underlying mechanism of RBM8A causing TAR syndrome, thereby enabling development of effective treatments. Our ultimate mission is to develop innovative strategies for prevention and treatment of structural abnormality disorders such as TAR syndrome. As an important step towards our goal, we have developed Rbm8a conditional knockout (cKO) mice and have revealed fascinating developmental defects. The objectives of our research are twofold: first, to examine the role of RBM8A in forelimb development, and second, to harness the power of viral gene therapy to reverse radial development defects in a TAR mouse model. Our rationale for this project is that its successful completion would provide a strong, conceptual, evidence-based framework to develop therapeutic strategies for congenital skeletal diseases. To achieve our objectives, we will rigorously test two Specific Aims: 1) Determine the role of Rbm8a in radial development; and 2) Determine the effects of RBM8A reinstatement therapy on anatomical and functional outcomes in cKO mice. At the completion of this project, we expect to discover important insights on the molecular basis of the radial development of a causal gene of TAR syndrome. The successful completion of the proposed studies would have an important positive impact on future drug screening and further development of novel therapeutic interventions for other developmental disorders.

项目总结