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.

项目摘要涉及骨骼和颅面发育的先天缺陷是最常见的人类之一具有未满足医疗需求的先天性疾病。最近的遗传学研究已经确定了多个鲁棒和可复制的风险基因座与这些毁灭性异常相关，为受苦者提供了新的希望。其中的发现，RBM8A中的突变引起了一种罕见的疾病，称为血小板减少症 - 不足 - 半径（焦油）综合征。 RBM8A基因编码RNA结合蛋白，但是确切的机制 RBM8A缺乏会导致组织特异性异常仍然被神秘覆盖。特别是 RBM8A骨骼畸形发生及其在骨发育中的直接靶标的缺乏尚不清楚。因此，迫切需要阐明RBM8A的基本机制，从而导致焦油综合征，从而实现有效治疗的发展。我们的最终任务是制定创新策略用于预防和治疗结构异常疾病，例如焦油综合征。作为重要的一步为了达到目标，我们开发了RBM8A有条件淘汰（CKO）小鼠，并揭示了令人着迷的发展缺陷。我们研究的目标是双重的：首先，检查RBM8A在前肢发育，其次是利用病毒基因疗法的力量逆转径向发育焦油鼠标模型中的缺陷。我们对该项目的理由是，其成功完成将提供强，概念性的，基于证据的框架来制定先天性骨骼的治疗策略疾病。为了实现我们的目标，我们将严格测试两个具体目标：1）确定RBM8A的作用径向发育； 2）确定RBM8A恢复疗法对解剖学和 CKO小鼠的功能结果。该项目完成后，我们希望发现重要的见解焦油综合征因果基因的径向发育的分子基础。成功完成在拟议的研究中，将对未来的药物筛查产生重要的积极影响开发针对其他发育障碍的新型治疗干预措施。