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：
10381615
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 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10381615
关键词：
Affect African Amino Acids Animal Model Binding Biochemical Biology Cardiac Caring Child Health 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 base 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发导致越来越多的基因组疾病被鉴定出来。先天性缺陷患者的基因组变异。但详细分析如何影响发育过程的变异很少，导致分类的变异类别不断增加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，并扩展我们的生物学知识以及参与疾病过程的分子的机械操作。在这个提案中，我们计划采用多学科方法来研究与先天性遗传相关的 YWHAZ 变异综合症。我们对从 RAS 病患者身上发现的一种变异进行的初步研究表明在脊椎动物中，该变体比野生型 YWHAZ 更有效地激活 RAF-ERK 通路动物模型，非洲爪蛙爪蟾。结果首次表明，YWHAZ 变异可能导致 RASopathies 的病因学。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非洲爪蟾模型的优势、生化和结构的力量研究，以及用于 YWHAZ 详细表征的小鼠遗传系统的强度变种。我们将调查 YWHAZ 变体是否以及如何改变活动（目标 1），如何改变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中的病理学（目标 3）。我们的调查团队与不同研究学科的专业知识有望对疾病产生深刻的洞察力相关的YWHAZ基因功能和机制。