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.

基因组医学研究的最新爆炸已导致确定越来越多的先天性缺陷患者的基因组变异。但是，详细分析了有关如何变体影响发育过程很少，从而导致一类归类的变体类别不断增长作为不确定意义的变体（VUS）。了解VUS的功能后果将有所帮助患者，他们的家人和医生学习病情的遗传基础，启用临床医生提供个性化的医疗和治疗，并扩大我们对生物学的了解和疾病过程中涉及的分子的机械操作。在此提案中，我们计划采用多学科方法来调查与先天性相关的YWHAZ变体综合征。我们对从患有Rasopathy患者发现的一种变体的初步研究显示该变体比脊椎动物中的野生型YWHAZ更有效地激活RAF-ERK途径动物模型，非洲爪的青蛙爪蟾。结果首次表明ywhaz 变体可能有助于病因。其他几个YWHAZ变体也与人类疾病，但尚未检查变体的功能意义。我们提出的研究将利用爪蟾模型的优势，即生化和结构的力量研究以及小鼠遗传系统的强度，以详细表征YWHAZ 变体。我们将调查YWHAZ变体是否以及如何改变活动（AIM 1），如何改变序列变化影响蛋白质结构和相互作用（AIM 2），以及变体如何诱导小鼠模型中的病理（AIM 3）。我们调查团队的新颖组合与不同研究学科的专业知识有望产生对疾病的深刻见解 - 相关的YWHAZ基因功能和机制。