Craniofacial Defects in the Manta-Ray Line: A Novel Model for Ribosomopathies

蝠鲼线颅面缺陷：核糖体病的新模型

• 批准号: 8991050
• 负责人: Konstantinos Zarbalis
• 金额: $ 38.72万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8991050
• 关键词: Affect; Anabolism; Apoptosis; Biogenesis; Brain; Cell Cycle Arrest; Cell Cycle Progression; Cell Cycle Regulation; Cell Death; Cell Proliferation; Cells; Cephalic; Characteristics; Cleaved cell; Cleft Palate; Clinical; Complement; Congenital Abnormality; Craniofacial Abnormalities; Defect; Development; Diamond-Blackfan anemia; Disease; Embryo; Etiology; Event; Exhibits; Face; Female; Fibroblasts; Frontonasal Prominence; Functional disorder; Generations; Genes; Genetic; Genetic Screening; Genetic Translation; Genetic screening method; Goals; Growth; Health; Hearing; Human; Jaw; Label; Lead; Life; Live Birth; Mandibulofacial Dysostosis; Mediating; Mediator of activation protein; Mental Retardation; Mesenchymal; Modeling; Molecular; Morphology; Mus; Mutate; Mutation; Names; Neural Crest; Neural Crest Cell; Neurodevelopmental Problem; Neuroepithelial Cells; Pathway interactions; Patients; Pattern; Phenotype; Polymerase Chain Reaction; Polyribosomes; Prevention; Process; Protein Kinase; Proteins; Reconstructive Surgical Procedures; Reverse Transcription; Ribosomes; Risk Factors; Role; Secondary Palate; Speech; Staging; Structure; Syndrome; Testing; Therapeutic; Time; Tissues; Translations; Tumor Suppressor Proteins; Up-Regulation; biological adaptation to stress; cleft lip and palate; clinical phenotype; craniofacial; craniofacial development; cyclin G1; feeding; inhibitor/antagonist; insight; migration; molecular marker; mutant; neoplastic cell; novel; novel therapeutic intervention; oral cleft; orofacial cleft; particle; pifithrin; pregnant; prevent; research study; response; tumor

DESCRIPTION (provided by applicant): Clefts of lip and palate are among the most common birth defects, occurring in approximately every 700 live births. Although treatable by reconstructive surgery, oral clefts cause complications early in life ranging from feeding problems to hearing and speech defects. In addition, many of these patients also show mental retardation or other neurodevelopmental problems. In a forward genetic screen carried out in mice we recovered a novel line named manta-ray (mray), which displays severe developmental defects including a median cleft of the upper jaw and secondary palate as well as abnormal brain development. We identified the causative recessive mutation in the Pak1ip1 gene, which encodes a preribosomal factor required for ribosome biogenesis. Loss of Pak1ip1 activates the tumor suppressor and cell cycle control factor Tp53, which leads to cell cycle arrest and cell death. This pathway appears to be a critical mediator of many of the clinical features of ribosomopathies including their craniofacial anomalies. Our current understanding of Pak1ip1 function strongly supports the hypothesis that Pak1ip1- deficiency in homozygous mray mutants activates the Tp53 pathway and leads to Tp53-mediated loss of cranial neural crest cells, which results in midline clefting. The experiments we propose here, will uncover the mechanisms that cause the craniofacial anomalies of homozygous mray mutants by providing a detailed analysis of neuroepithelial cell death, proliferation, and specification of neural crest-derived tissues. In second set of experiments, we will attempt to ameliorate or even rescue the midline cleft in affected mutants by inhibiting Tp53 response either through pharmacological or genetic means. Finally, we will examine the way the mray mutation affects the process of ribosome biogenesis in general and in particular, by analyzing specific deficits in the translation of midface-specific growth factors. In summary, our study will provide substantial new insight into the mechanisms by which defects in ribosome biogenesis can lead to craniofacial birth defects, which are common and clinically important and will explore treatment options by interfering with the Tp53 pathway.

描述(申请人提供)：唇腭裂是最常见的出生缺陷之一，大约每700名活产儿中就会发生一例。虽然口腔裂可以通过重建手术治疗，但它会在生命早期导致并发症，从喂养问题到听力和言语缺陷。此外，这些患者中的许多人还表现出智力低下或其他神经发育问题。在对小鼠进行的正向遗传筛查中，我们发现了一种名为螳螂(Mray)的新品系，该品系显示出严重的发育缺陷，包括上颌和次级腭裂以及大脑发育异常。我们鉴定了Ak1ip1基因的致病隐性突变，该基因编码核糖体生物发生所需的胸前因子。Ak1ip1的缺失激活了肿瘤抑制因子和细胞周期控制因子TP53，导致细胞周期停滞和细胞死亡。这一通路似乎是核糖体疾病的许多临床特征的关键媒介，包括它们的颅面部异常。我们目前对Pak1ip1功能的理解有力地支持了这一假说，即纯合子mray突变体中的pak1ip1缺失激活了TP53途径，导致TP53介导的脑神经脊细胞丢失，从而导致中线分裂。我们在这里提出的实验，将通过对神经上皮细胞死亡、增殖和神经脊来源组织的规范的详细分析，揭示导致纯合子mray突变的头面部异常的机制。在……里面 第二组实验，我们将试图通过药理学或遗传手段抑制TP53的反应，以改善甚至挽救受影响突变体的中线裂隙。最后，我们将研究mray突变影响核糖体生物发生过程的一般方式，特别是通过分析中面特定翻译的特定缺陷。 增长因素。综上所述，我们的研究将为核糖体生物发生缺陷导致头面部出生缺陷的机制提供实质性的新见解，这是一种常见的临床重要的出生缺陷，并将通过干扰TP53途径来探索治疗方案。