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Functional and mechanistic characterization of YWHAZ variants associated with human diseases

与人类疾病相关的 YWHAZ 变异的功能和机制特征

基本信息

批准号：
10610892
负责人：
CHENBEI CHANG
金额：
$ 57.1万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10610892
关键词：
Affect African Amino Acids Animal Model Binding Biochemical Biology Cardiac Caring Child Health Classification Code Congenital Abnormality Congenital Disorders Counseling Developmental Process Diagnosis Discipline Disease Distress Economics Emotional Etiology Explosion Family Generations Genes Genetic Genetic Variation Genetic study Genome Genomic medicine Genomics Human In Vitro Investigation Knowledge Learning Length Link MEKs Medical Medicine Modeling Molecular Morphology Pathogenicity Pathology Pathway interactions Patient Care Patients Phosphopeptides Physiological Process Proteins Research Research Personnel Societies Structure Syndrome System Technology Time Variant Vertebrates Work Xenopus clinical phenotype cognitive ability congenital anomaly craniofacial experimental study gene function genetic counselor genetic variant genome analysis genomic variation human disease human genome sequencing improved in vivo Model insight interdisciplinary approach mouse genetics mouse model neurodevelopment novel operation patient variability protein structure structural biology variant of unknown significance xenopus development

项目摘要

Recent explosion in genomic medicine studies has led to identification of an increasing number of genomic variations from patients with congenital defects. However, detailed analyses about how the variants affect developmental processes are scarce, resulting in a growing class of variants classified as variants of uncertain significance (VUS). Understanding functional consequences of VUS will help patients, their families, and their doctors to learn genetic underpinnings of their conditions, enable clinicians to provide personalized medical care and treatment, and expand our knowledge on biology and mechanistic operations of the molecules involved in disease processes. In this proposal, we plan to employ multidisciplinary approaches to investigate the YWHAZ variants associated with congenital syndromes. Our preliminary studies on one variant identified from a patient with RASopathy revealed that the variant activated the RAF-ERK pathway more efficiently than wild type YWHAZ in a vertebrate animal model, the African clawed frog Xenopus. The results show for the first time that YWHAZ variant may contribute to etiology of RASopathies. Several other YWHAZ variants also associate with human disorders, but functional significance of the variants has not been examined. Our proposed research will leverage the advantages of the Xenopus model, the power of biochemical and structural studies, and the strength of the mouse genetic system for detailed characterization of the YWHAZ variants. We will investigate whether and how YWHAZ variants have altered activities (aim 1), how sequence variations affect protein structure and interaction (aim 2), and how the variants induce pathology in the mouse models (aim 3). The novel combination of our investigation teams with expertise in distinct research disciplines promises generation of profound insight into disease- associated YWHAZ gene function and mechanisms.

最近基因组医学研究的爆炸性增长导致越来越多的先天缺陷患者的基因组变异。然而，详细的分析表明影响发育过程的变异很少，导致分类的变异越来越多作为不确定意义的变体(VU)。了解VU的功能后果将有所帮助患者、他们的家人和他们的医生了解他们病情的遗传基础，使临床医生提供个性化的医疗护理和治疗，并扩大我们的生物学知识以及疾病过程中涉及的分子的机械性操作。在这份提案中，我们计划采用多学科方法研究与先天性疾病相关的YWHAZ变异综合症。我们对一例类风湿关节炎患者的一种变异体的初步研究揭示在脊椎动物中，该变体比野生型YWHAZ更有效地激活RAF-ERK途径动物模型，非洲爪蛙非洲爪蛙。结果首次表明，YWHAZ 变异体可能与Rasopathies的病因学有关。其他几个YWHAZ变种也与人类疾病，但变异体的功能意义尚未得到检验。我们的建议研究将利用非洲爪哇模式的优势，生化和结构的力量研究，以及小鼠遗传系统的力量，以详细描述YWHAZ 变种。我们将调查YWHAZ变体是否以及如何改变了活动(目标1)，如何序列变异影响蛋白质结构和相互作用(目标2)，以及变异如何诱导小鼠模型的病理学(目标3)。我们的调查团队与不同研究学科的专业知识有望产生对疾病的深刻洞察- 相关的YWHAZ基因的功能和机制。