Modeling the molecular and cellular mechanisms of TE birth defects in animals
Modeling the molecular and cellular mechanisms of TE birth defects in animals
批准号:
10174985
负责人:
Aaron M Zorn
金额:
$32.4万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-08-15 至 2022-05-31
关键词:
Animal ModelAnimalsAutomobile DrivingBirthBreathingCandidate Disease GeneCell Culture TechniquesCell physiologyClustered Regularly Interspaced Short Palindromic RepeatsComplementCongenital AbnormalityCystic kidneyDataDefectDevelopmentDiagnosisDifferentiation and GrowthEmbryoEpithelialErinaceidaeEsophageal AtresiaEsophageal TissueEsophagusEtiologyEventExhibitsFetal DevelopmentGene MutationGenesGeneticGoalsHumanHuman GeneticsLeadLifeMediatingMesenchymalModelingMolecularMorphogenesisMusMutationNewborn InfantOperative Surgical ProceduresOrthologous GenePathway interactionsPatient CarePatientsPatternPhenotypePrimitive foregut structureProcessRegulator GenesRoleStructureSystemTestingTimeTracheaTracheal AtresiaTracheoesophageal FistulaTubeWorkXenopuscomorbidityfeedinggene functiongenetic testinggenetic variantgenome editinghuman modelhuman pluripotent stem cellimprovedinnovationknock-downmaturity onset diabetes of the youngmodel organisms databasesmolecular modelingmouse geneticsmutantneonatal periodnovelpreventtranscription factortranscriptome
中文摘要
气管导管和食道导管(TE)是由胎儿早期发育的单一输卵管引起的。这些缺陷是由TE引起的。
形态发生可能导致一系列危及生命的先天性气管-食道和出生缺陷综合征(TEDS)。
防止新生儿呼吸困难或喂养困难。这一项目的主要目标是进一步确定婴儿的分子水平。
以及使用不同动物模型的TEDs的细胞学基础。在第一个新生儿时期,TEDs是通过手术矫正的。
TEDS通常与长期的共同发病率有关。通常发生在出生后约1:3500的婴儿中,其病因学特征很差。
明白。尽管有证据表明这是一种主要的遗传基因成分,但已知的14种基因的突变是导致这种疾病的主要原因。
只有12%的患者患有食道闭锁和/或气管-食道瘘(EA/TEF)[1],而这是主要的遗传因素。
更多罕见和致命性气管闭锁综合征(TA)的基础尚不清楚。这些零星的DNA突变发生在大约25个额外的遗传基因中。
已经被证实与EEA/TEF患者有关,但这些研究仍有待进一步验证。已证明可以使用。
对TED、BMP和BMP进行有效的建模表明,对于Hedgehog基因(HH)基因和BMP基因通路,以及其他突变体来说,这是一个关键的基因角色。
表现出这些缺陷的情况类似于人类的患者。尽管取得了这些进展,但在这一领域仍然存在大量的缺陷。
小鼠基因是一种相对较低的基因吞吐能力的模型,而且只有少数几个来自患者的候选基因突变尚未被发现。
到目前为止已经过验证。第二,虽然HH基因和BMP基因可能与细胞形态发生有关,但它们的主要细胞调控机制却并非如此。
调节和控制胃管进入食道和气管的分离情况也是未知的。但这一点是可能的。
因为这些事件都会发生在胎儿胚胎发育的早期,也就是小鼠胚胎在体内发育的时候。
在我们的初步数据中,我们已经确定了非洲爪哇的胚胎是一种生物。
为了补充小鼠的遗传学,创新的高通量基因模型已经开始寻找新的基因和基因。
保守的控制细胞形态发生的细胞调控机制。这些研究将引导我们提出可能导致HH的假说。
骨形态发生蛋白和骨形态发生蛋白相互作用,以调节细胞的形态发生过程,以及在这些过程中发生的突变。
路径将产生一系列不同的表型,这些表型将成为人类TEDs的模型。但这个新的项目将不会定义TEDs。
未来发展的分子生物学和细胞生物学机制,将定义TED的主要结构和基础,并检验其推定的生物学基础。
TED-导致的基因突变来自大多数患者(项目-1)。最终,这项研究不仅将改善诊断,还将加强对患者的护理。
并向我们提供从人类非多能干细胞(HPSCs)中生成新的组织细胞的战略(项目-3)。
目的:1刻画动物特殊形态发生的主要细胞生物学机制。
目的:2确定HH-gli基因和BMP-Sox2基因通路中的缺陷是如何扰乱细胞形态发生的。
Aim-3验证候选的TED-导致非洲爪哇和小鼠的基因突变。
英文摘要
The trachea and esophagus (TE) arise from a single foregut tube in early fetal development. Defects in TE
morphogenesis result in a spectrum of life-threatening congenital tracheo-esophageal birth defects (TEDs) that
prevent proper breathing or feeding in newborns. The goal of this project is to determine the molecular
and cellular basis of TEDs using animal models. Corrected surgically in the neonatal period, TEDs are
often associated with long-term co-morbidity. Occurring in ~1:3500 births, the etiology of TEDs is poorly
understood. Although evidence indicates a major genetic component, known mutations in 14 genes account for
only 12% of patients with esophageal atresia and/or tracheoesophageal fistula (EA/TEF) [1], while the genetic
basis of more rare and lethal tracheal atresia (TA) is unknown. Sporadic mutations in ~25 additional genes
have been associated with EA/TEF patients, but these remain to be validated. Mouse has proven to be
effective for modeling TEDs, and indicates a key role for the Hedgehog (HH) and BMP pathways, with mutants
exhibiting defects similar to human patient. Despite this progress there are a number of limitations in the field.
Mouse is a relatively low throughput model and only a few of candidate mutations from patients have been
validated to date. Second, while HH and BMP are implicated TE morphogenesis the cellular mechanisms they
regulate, to control separation of the foregut tube into esophagus and trachea are unknown. This is in part
because these events occur early in fetal development when internally developing mouse embryos are
challenging to manipulate and visualize. In preliminary data we have established Xenopus embryos as an
innovative high-throughput model to complement mouse genetics, and have begun to identify novel and
conserved cellular mechanisms controlling TE morphogenesis. These studies lead us to hypothesize that HH
and BMP interact to regulate the cellular processes of TE morphogenesis and that mutations in these
pathways result in a spectrum of phenotypes that model human TEDs. This project will define the
molecular and cellular mechanisms of TE development, define the structural basis of TEDs and test putative
TED-causing mutations from patients (project-1). Ultimately this will improve diagnosis, enhance patient care,
and inform strategies to generate TE tissue from human pluripotent stem cells (hPSCs) (project-3).
Aim 1 Characterize the cellular mechanisms of TE morphogenesis in animals.
Aim 2 Determine how defects in HH-Gli and BMP-Sox2 pathways disrupt TE morphogenesis.
Aim 3 Validate candidate TED-causing mutations in Xenopus and mouse.
期刊论文(0)
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科研奖励(0)
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