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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：
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炸式增长导致越来越多的疾病被发现