A system approach to the analysis of Heterotaxy Candiate Genes

分析异序候选基因的系统方法

基本信息

批准号：
8898862
负责人：
Mustafa K Khokha
金额：
$ 51.45万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8898862
关键词：
Address Affect Alleles Biological Assay Biological Models Biology Candidate Disease Gene Categories Cause of Death Child health care Childhood Cilia Clustered Regularly Interspaced Short Palindromic Repeats Congenital Abnormality Development Developmental Biology Developmental Process Disease Embryonic Development Environmental Exposure Etiology Europe Failure Future Gene Expression Genes Genetic Genetic Counseling Genetic Predisposition to Disease Genetic Screening Genetic screening method Genomics Goals Grant Growth Health Heart Heterogeneity Human Human Genetics Immune Individual Infant Infant Mortality Lead Left Link Liver Lung Modeling Names Nature Organ Pathology Pathway interactions Patients Pattern Play Regulator Genes Role Signal Pathway Signal Transduction Signaling Pathway Gene Situs Inversus Sorting - Cell Movement Spleen Staging Structural Congenital Anomalies System Systems Biology Testing Time Transforming Growth Factor beta Validation Xenopus base congenital heart disorder falls fitness gain of function gene function genetic analysis genetic pedigree improved interest loss of function notch protein novel overexpression prognostic

项目摘要

DESCRIPTION (provided by applicant): Congenital malformations are the major cause of infant mortality in the US and Europe. However, we have a poor understanding of the genetic causes of congenital malformations. In order to discover these genetic causes, we and others have employed human genomics analyses on patients. In particular we have focused on Heterotaxy, a disorder of left-right patterning. Normally, our internal organs are asymmetrically distributed along the left-right axis and failure to do so can lead to severe disease including congenital heart disease, gut malrotation, and immune deficiencies. Human genetic analysis of these patients has identified many candidate genes, but the functional relevance of these genes is unclear since strong genetic evidence (second unrelated alleles) is not available for most of them. In addition, these genes are diverse and do not fall into clear pathways~ in fact, the vast majority of these candidate genes are novel to left-right patterning. For this reason, we propose a systems approach to the analysis of these heterotaxy candidate genes. We will first prioritize these genes based on available genetic evidence and then use an unbiased approach, which will include gene expression, gain of function, and loss of function analysis to determine which of these genes play a role in left- right patterning using our high-throughput model, Xenopus. Our preliminary results indicate that many but not all of these candidate genes are important for left-right patterning. Then we will take an unbiased systems approach to placing these heterotaxy candidate genes into the left-right signaling gene regulatory network. Our preliminary results demonstrate that this systems approach identifies unexpected and interesting bridges between different pathways and identifies functions not otherwise expected of known gene and identifies specific functions of genes with no known function. In this way, we hope to improve our understanding of heterotaxy and develop a general model to approach many congenital malformations.

描述（由申请人提供）：先天性畸形是美国和欧洲婴儿死亡率的主要原因。但是，我们对先天性畸形的遗传原因的理解很差。为了发现这些遗传原因，我们和其他人对患者进行了人类基因组学分析。特别是我们专注于异性恋，这是一种左右模式的疾病。通常，我们的内部器官沿左右轴不对称，并且不这样做会导致严重疾病，包括先天性心脏病，肠道畸形和免疫缺陷。这些患者的人类遗传分析已经确定了许多候选基因，但是这些基因的功能相关性尚不清楚，因为大多数人都无法使用强大的遗传证据（第二个无关等位基因）。此外，这些基因是多种多样的，并且不会陷入清晰的途径〜实际上，很大这些候选基因中的大多数是新颖的左右图案。因此，我们提出了一种系统方法来分析这些异Xy候选基因。我们将基于可用的遗传证据首先优先考虑这些基因，然后使用公正的方法，其中包括基因表达，功能获得和功能分析的丧失，以确定这些基因的哪个基因在使用我们的高通量模型xenopus中在左右构图中起作用。我们的初步结果表明，许多但并非所有这些候选基因对于左右模式都很重要。然后，我们将采用一种无偏的系统方法，将这些异质候选基因置于左右信号传导基因调节网络中。我们的初步结果表明，这种系统方法可以识别不同途径之间的意外且有趣的桥梁，并识别未预期的已知基因的功能，并确定没有已知功能的基因的特定功能。通过这种方式，我们希望提高对异性恋的理解，并开发出一种处理许多先天性畸形的通用模型。