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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）：先天畸形是美国和欧洲婴儿死亡的主要原因。然而，我们对先天性畸形的遗传原因知之甚少。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。我们特别关注异向性，一种左右模式紊乱。正常情况下，我们的内脏器官沿着左右轴不对称分布，如果不这样做，可能会导致严重的疾病，包括先天性心脏病、肠道旋转不良和免疫缺陷。对这些患者的人类遗传分析已经确定了许多候选基因，但这些基因的功能相关性尚不清楚，因为大多数基因都没有强有力的遗传证据（第二个不相关的等位基因）。另外，这些基因是多种多样的，并不属于明确的通路~事实上，这些候选基因中的大多数对于左右模式来说都是新颖的。为此，我们提出了一种系统方法来分析这些异位候选基因。我们将首先根据现有的遗传证据对这些基因进行优先排序，然后使用公正的方法，其中包括基因表达、功能获得和功能丧失分析，以确定这些基因中哪些基因在使用我们的高通量模型非洲爪蟾的左右模式中发挥作用。我们的初步结果表明，许多但不是全部这些候选基因对于左右模式都很重要。然后我们将采用无偏系统方法将这些异位候选基因放入左右信号基因调控网络中。我们的初步结果表明，这种系统方法识别了不同途径之间意想不到的和有趣的桥梁，识别了已知基因未预期的功能，并识别了未知功能的基因的特定功能。通过这种方式，我们希望提高我们对异型的理解，并开发一个通用模型来处理许多先天畸形。