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.

项目摘要 先天性心脏病（CHD）是由于先天缺陷而导致的最常见死亡原因。尽管有频率 识别冠心病的遗传原因一直具有挑战性。 Mendelian的遗传（非元素）CHD 很少见。取而代 可能的寡原作用。尽管基因组广泛的关联研究，三重奏和基于家庭的研究一直是 利用，很少强调检查上毒，加性效应或突变负担。 此外，尽管对心脏发育的理解得到了改善，已经确定了基因和途径 在动物模型中，这是CHD的基础，这些知识并不总是很容易转化为对 人类冠心病的疾病因果关系。为了提高我们预测CHD和预后风险的能力，这是 重要的是确定有助于零星冠心病并整合功能基因组学的新基因和途径 用于具有发展生物学的变体分析，以进行机理理解。我们建议解决这些问题 通过调查新的基因，导致心脏畸形，chroom3和划定的关键需求 它的相互作用组，作为利用人类基因组学和发育生物学的典范。这个目的 研究是：1）检验以下假设：心脏发生需要shroom3与平面细胞极性相互作用 （PCP）蛋白质和下游效应子。该目标的结果将识别细胞和组织特异性 Shroom3丢失的后果，确定其相互作用组和其遗传相互作用在CHD上的后果； 2）检验以下假设：编码PCP信号和下游效应蛋白的基因中的罕见变异 富含冠心病患者。此目标的结果将在功能上验证shroom3稀有变体 并确定对CHD易感性重要的基因和途径。结合功能 基因组学来定义稀有变体的影响，使用小鼠模型的机械研究以及人类遗传学的影响， 这些研究将共同​​定义shroom3在心脏发展中的作用以及 Shroom3和PCP途径成员成为CHD的遗传结构。