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:
- 金额:$ 51.45万
- 依托单位:
- 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:
- 关键词:AddressAffectAllelesBiological AssayBiological ModelsBiologyCandidate Disease GeneCategoriesCause of DeathChild health careChildhoodCiliaClustered Regularly Interspaced Short Palindromic RepeatsCongenital AbnormalityDevelopmentDevelopmental BiologyDevelopmental ProcessDiseaseEmbryonic DevelopmentEnvironmental ExposureEtiologyEuropeFailureFutureGene ExpressionGenesGeneticGenetic CounselingGenetic Predisposition to DiseaseGenetic ScreeningGenetic screening methodGenomicsGoalsGrantGrowthHealthHeartHeterogeneityHumanHuman GeneticsImmuneIndividualInfantInfant MortalityLeadLeftLinkLiverLungModelingNamesNatureOrganPathologyPathway interactionsPatientsPatternPlayRegulator GenesRoleSignal PathwaySignal TransductionSignaling Pathway GeneSitus InversusSorting - Cell MovementSpleenStagingStructural Congenital AnomaliesSystemSystems BiologyTestingTimeTransforming Growth Factor betaValidationXenopusbasecongenital heart disorderfallsfitnessgain of functiongene functiongenetic analysisgenetic pedigreeimprovedinterestloss of functionnotch proteinnoveloverexpressionprognostic
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Mustafa K Khokha其他文献
Mustafa K Khokha的其他文献
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{{ truncateString('Mustafa K Khokha', 18)}}的其他基金
Potassium channels, membrane potential, and CHD
钾通道、膜电位和 CHD
- 批准号:
10439505 - 财政年份:2020
- 资助金额:
$ 51.45万 - 项目类别:
A system approach to the analysis of Heterotaxy Candidate Genes
分析异序候选基因的系统方法
- 批准号:
10558564 - 财政年份:2020
- 资助金额:
$ 51.45万 - 项目类别:
A system approach to the analysis of Heterotaxy Candidate Genes
分析异序候选基因的系统方法
- 批准号:
10359821 - 财政年份:2020
- 资助金额:
$ 51.45万 - 项目类别:
Potassium channels, membrane potential, and CHD
钾通道、膜电位和 CHD
- 批准号:
10614586 - 财政年份:2020
- 资助金额:
$ 51.45万 - 项目类别:
New Mechanisms of Heterotaxy and Congenital Heart Disease: Nucleoporins at Cilia
异向性与先天性心脏病的新机制:纤毛核孔蛋白
- 批准号:
10237134 - 财政年份:2015
- 资助金额:
$ 51.45万 - 项目类别:
New Mechanisms of Heterotaxy and Congenital Heart Disease: Nucleoporins at Cilia
异向性与先天性心脏病的新机制:纤毛核孔蛋白
- 批准号:
10443780 - 财政年份:2015
- 资助金额:
$ 51.45万 - 项目类别:
A system approach to the analysis of Heterotaxy Candiate Genes
分析异序候选基因的系统方法
- 批准号:
8766951 - 财政年份:2014
- 资助金额:
$ 51.45万 - 项目类别:
Characterization and cloning of X. tropicalis Craniofacial Mutants
热带 X. 热带菌颅面突变体的表征和克隆
- 批准号:
7932553 - 财政年份:2009
- 资助金额:
$ 51.45万 - 项目类别:
Developing transposon methods for insertional mutagenesis in Xenopus
开发非洲爪蟾插入突变的转座子方法
- 批准号:
7895047 - 财政年份:2009
- 资助金额:
$ 51.45万 - 项目类别:
Characterization and cloning of X. tropicalis Craniofacial Mutants
热带 X. 热带菌颅面突变体的表征和克隆
- 批准号:
7342329 - 财政年份:2008
- 资助金额:
$ 51.45万 - 项目类别:
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