Delineating molecular mechanism of developmental defects of TAR syndrome

描绘 TAR 综合征发育缺陷的分子机制

• 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
• 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

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出生缺陷是人类最常见的缺陷之一 医疗需求未得到满足的先天性疾病。最近的遗传学研究已经确定了多种强大的， 可复制的风险位点与这些毁灭性的异常有关，为那些受影响的人提供新的希望。 其中一项发现是，RBM8A的突变会导致一种罕见的疾病，称为血小板减少症， 桡骨综合征。RBM8A基因编码一种RNA结合蛋白，但其确切机制是 RBM8A缺乏导致组织特异性异常仍然是一个谜。特别是， RBM8A缺乏在骨骼畸形中的作用及其在骨发育中的直接靶点仍不清楚。 因此，迫切需要阐明RBM8A引起TAR综合征的潜在机制， 从而能够开发有效的治疗方法。我们的最终使命是制定创新战略 用于预防和治疗结构异常疾病如TAR综合征。作为一个重要步骤 为了实现我们的目标，我们开发了Rbm8a条件性敲除（cKO）小鼠，并揭示了令人着迷的 发育缺陷我们的研究目标是双重的：首先，检查RBM8A在 前肢发育，第二，利用病毒基因治疗的力量来逆转辐射状发育 TAR小鼠模型中的缺陷。我们开展该项目的理由是，它的成功完成将为我们提供 一个强有力的、概念性的、以证据为基础的框架，以制定先天性骨骼肌畸形的治疗策略 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 2）确定RBM8A恢复疗法对桡骨发育的解剖学和组织学的影响。 cKO小鼠的功能结果。在这个项目完成后，我们希望发现重要的见解， TAR综合征致病基因放射状发育的分子基础。圆满完成 拟议的研究将对未来的药物筛选产生重要的积极影响， 为其他发育障碍开发新的治疗干预措施。