Developmental and genetic function of SHROOM3

SHROOM3的发育和遗传功能

• 批准号: 10587298
• 负责人: Stephanie M Ware
• 金额: $ 53.09万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587298
• 关键词: Actomyosin; Address; Animal Model; Apical; Binding; Biological Assay; Cause of Death; Cell Lineage; Cell Polarity; Cells; Child; Congenital Abnormality; Congenital Heart Defects; Cytoskeleton; Data; Defect; Development; Developmental Biology; Disease susceptibility; Embryonic Heart; Etiology; Exhibits; Family; Frequencies; Genes; Genetic; Genetic Epistasis; Genetic Predisposition to Disease; Genomics; Heart Abnormalities; Heterozygote; Human; Human Genetics; Immunoprecipitation; In Vitro; Indiana; Investigation; Knowledge; Lead; Link; Mass Spectrum Analysis; Movement; Mus; Mutate; Mutation; Outcome; Pathway interactions; Patients; Pediatric Cardiac Genomics Consortium; Penetrance; Phenocopy; Phenotype; Predisposition; Prognosis; Proteins; Rho-associated kinase; Role; Shapes; Signal Pathway; Signal Transduction; Technology; Testing; Tissues; Translating; Variant; Ventricular Septal Defects; Xenopus; biobank; cardiogenesis; cell motility; cohort; congenital heart disorder; constriction; developmental genetics; disease phenotype; exome; exome sequencing; functional genomics; genetic architecture; genetic testing; genetic variant; genome sequencing; genome wide association study; human disease; human genomics; human model; improved; in vivo; member; mouse model; novel; planar cell polarity; protein protein interaction; public health relevance; rare variant; risk prediction; single-cell RNA sequencing; transcriptome sequencing; whole genome

PROJECT SUMMARY Congenital heart disease (CHD) is the most common cause of death due to birth defects. Despite its frequency, identifying genetic causes of CHD has been challenging. Mendelian inheritance of sporadic (nonsyndromic) CHD is rare. Instead, the genetic architecture of CHD is characterized by non-penetrance, variable expressivity, and likely oligogenic effects. Although genome wide association studies, trio, and family-based studies have been utilized, there has been little emphasis on examining epistasis, additive effects, or mutational burden. Furthermore, although an improved understanding of cardiac development has identified genes and pathways that underlie CHD in animal models, this knowledge has not always translated readily into an understanding of disease causation in human CHD. In order to improve our ability to predict risk for CHD and prognosis, it is important to identify new genes and pathways that contribute to sporadic CHD and integrate functional genomics for variant analysis with developmental biology for mechanistic understanding. We propose to address these critical needs through investigation of a novel gene causing cardiac malformations, SHROOM3, and delineation of its interactome, as an exemplar leveraging human genomics and developmental biology. The aims of this study are to: 1) test the hypothesis that cardiogenesis requires SHROOM3 interaction with planar cell polarity (PCP) proteins and downstream effectors. The outcome of this aim will identify cell- and tissue-specific consequences of loss of Shroom3, identify its interactome and consequence of its genetic interactions on CHD; and 2) test the hypothesis that rare variants in genes encoding PCP signaling and downstream effector proteins are enriched in patients with CHD. The outcome of this aim will functionally validate SHROOM3 rare variants and identify genes and pathways important for the susceptibility to CHD. Using a combination of functional genomics to define the impact of rare variants, mechanistic studies using mouse models, and human genetics, these studies will collectively define the role of SHROOM3 in heart development and the contribution of SHROOM3 and PCP pathway members to the genetic architecture of CHD.

项目总结