Etiology and pathogenesis of lethal lung developmental disorders in neonates
新生儿致命性肺发育障碍的病因和发病机制
基本信息
- 批准号:10660107
- 负责人:
- 金额:$ 79.34万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-15 至 2027-05-31
- 项目状态:未结题
- 来源:
- 关键词:AllelesAlveolarAlveolar capillary dysplasia with misalignment of pulmonary veinsAppearanceAutopsyBinding SitesBiological AssayBiopsyCell LineChIP-seqChildhoodChromosome 16ClassificationCodeComplexCongenital alveolar dysplasiaCopy Number PolymorphismDNA BindingDataDevelopmentDevelopmental GeneDiagnosisDiseaseDistantDysplasiaElectrophoretic Mobility Shift AssayEmbryoEndotheliumEnhancersEpitheliumEtiologyFGF10 geneFGFR2 geneFOXF1 geneFamilyGenesGeneticGenetic CounselingHeart AbnormalitiesHeterozygoteHistologicHistonesHumanHuman Cell LineHuman GeneticsInfantIntegral Membrane ProteinLifeLungMapsMediatingMediatorMesenchymalMesenchymeModificationMusMutateNucleic Acid Regulatory SequencesParacrine CommunicationPathogenesisPathogenicityPatientsPenetrancePhasePhenotypePlayProcessPrognosisPrognostic MarkerPromoter RegionsRNA InterferenceRegulatory ElementReportingResearchResolutionRoleSHH geneSignal PathwaySignal TransductionSignaling MoleculeSingle Nucleotide PolymorphismSpecimenTechniquesTechnologyTranslatingUntranslated RNAVariantdevelopmental diseasediagnostic biomarkerdisease phenotypefetalgenetic variantgenome editinghypoxia neonatorumin uteroinsightinterestlung developmentmalformationmouse modelneonatenovelnovel diagnosticspreventpromoterpulmonary arterial hypertensionpulmonary hypoplasiatherapeutic targettranscription factortranscriptome sequencing
项目摘要
Project Summary
Lethal lung developmental disorders (LLDDs) are rarely diagnosed but devastating pulmonary hypoplasias
(PHs), presenting with progressive neonatal hypoxia and severe pulmonary arterial hypertension (PAH). Based
on histopathological appearance, LLDDs have been traditionally classified as alveolar capillary dysplasia with
misalignment of pulmonary veins (ACDMPV), acinar dysplasia (AcDys), congenital alveolar dysplasia (CAD),
and other unspecified primary PHs. We found that heterozygous single nucleotide variants (SNVs) in the
mesenchymal transcription factor (TF) FOXF1 gene or copy-number variant (CNV) deletions involving FOXF1
or its lung-specific enhancer located ~ 300 kb upstream are responsible for ACDMPV in 80-90% of patients. We
reported that this enhancer also up-regulates in cis lncRNA FENDRR mapping nearby FOXF1. Interestingly,
unlike SNVs, CNV deletions arise almost exclusively on the maternal chromosome 16. Recently, we and others
demonstrated the causative role for variants in another mesenchymal TF, TBX4, and a paracrine signaling
molecule FGF10 in greater than 60% of infants with AcDys, CAD, and other primary PHs, indicating the
significance also of TBX4-FGF10 signaling in pathogenesis of LLDDs. Importantly, FOXF1 and TBX4 variants
have been associated also with more common idiopathic or familial childhood PAH. Interestingly, we found a
statistically significant enrichment of non-coding SNVs in the FOXF1 and TBX4 enhancers in patients with
variable presentation of LLDD. Moreover, our ChIP-seq and RNA-seq studies have implied interactions between
the SHH-FOXF1 and TBX4-FGF10 signaling pathways, involving little-known lung-specific endothelial
transmembrane protein TMEM100. We hypothesize that (i) non-coding SNVs within the regulatory regions of
lung developmental genes can dramatically modify (alleviate or exacerbate) LLDD and PAH phenotypes, (ii) an
interplay between the coding and non-coding variants can explain the complex compound inheritance observed
in families with LLDDs and PAH, and (iii) interaction of SHH-FOXF1 and TBX4-FGF10 signaling pathways,
involving TMEM100, is required for proper human lung development. Using human lung specimens and cell lines
and mouse models, we will identify and analyze non-coding regulatory elements of FOXF1 in patients with
ACDMPV and/or PAH (Aim 1) and those of TBX4 and FGF10 in patients with AcDys, CAD, other PHs, and/or
PAH (Aim 2). In Aim 3, we will decipher the crosstalk between SHH-FOXF1 and TBX4-FGF10 epithelial-
mesenchymal signaling, involving TMEM100, to untangle the complex compound inheritance in families with
LLDDs and PAH. Our studies will elucidate the genetics of lung development in humans and how its perturbations
translate to phenotypic variability of LLDDs and PAH. We will identify new genetic variants, allowing for more
precise diagnosis and prognosis of these disorders, facilitating more informative genetic counseling, and
providing targets for development of potential in utero treatments for LLDDs and PAH. Our data will also help to
better understand incomplete penetrance and variable expressivity phenomena in human genetics in general.
项目摘要
致死性肺发育障碍(LLDD)很少被诊断出来,但具有破坏性的肺发育不良。
(PHS),表现为进行性新生儿缺氧和严重的肺动脉高压(PAH)。基座
在组织病理学上,LLDDS传统上被归类为肺泡毛细血管异常增殖症
肺静脉错位(ACDMPV)、腺泡发育不良(AcDys)、先天性肺泡发育不良(CAD)、
和其他未指明的主要小灵通。我们发现杂合性单核苷酸变异(SNV)在
间质转录因子FOXF1基因或拷贝数变异(CNV)缺失涉及FOXF1
或其位于上游约300kb的肺特异性增强子在80-90%的患者中对ACDMPV起作用。我们
报道称,该增强子还上调了FOXF1附近的顺式lncRNA Fendrr图谱。有趣的是,
与SNV不同,CNV的缺失几乎完全发生在母亲的16号染色体上。最近,我们和其他人
证明了另一种间充质转铁蛋白、TBX4和旁分泌信号中的变异所起的作用
在患有AcDys、CAD和其他原发PHS的婴儿中,超过60%的婴儿存在FGF10分子,表明
Tbx4-FGF10信号在LLDDS发病机制中的意义。重要的是,FOXF1和TBX4的变种
也与更常见的特发性或家族性儿童PAH有关。有趣的是,我们发现了一个
慢性粒细胞白血病患者FOXF1和TBX4增强子中非编码SNV的显著丰富
LLDD的可变表示形式。此外,我们的CHIP-SEQ和RNA-SEQ研究暗示了
SHH-FOXF1和TBX4-FGF10信号通路,涉及鲜为人知的肺内皮细胞
跨膜蛋白TMEM100。我们假设(I)监管区域内的非编码SNV
肺发育基因可以显著改变(减轻或加重)LLDD和PAH的表型,(Ii)和
编码和非编码变体之间的相互作用可以解释观察到的复杂复合遗传
在LLDD和PAH家族中,以及(Iii)SHH-FOXF1和TBX4-FGF10信号通路的相互作用,
涉及TMEM100,是人类肺正常发育所必需的。使用人类肺标本和细胞系
和小鼠模型,我们将识别和分析FOXF1在慢性阻塞性肺疾病患者中的非编码调控元件。
ACDMPV和/或PAH(Aim 1)以及Tbx4和FGF10在AcDys、CAD、其他PHS和/或
PAH(目标2)。在目标3中,我们将破译SHH-FOXF1和TBX4-FGF10上皮细胞之间的串扰-
间充质信号,涉及TMEM100,以解开复杂的化合物遗传
LLDDS和PAH。我们的研究将阐明人类肺发育的遗传学以及它的扰动如何
转化为低密度脂蛋白和多环芳烃的表型变异。我们将识别新的基因变异,允许更多
对这些疾病的准确诊断和预后,促进更多信息丰富的遗传咨询,以及
为开发LLDDS和PAH的宫内治疗潜力提供目标。我们的数据还将有助于
更好地理解人类遗传学中的不完全外显和表达能力变化现象。
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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PAWEL STANKIEWICZ其他文献
PAWEL STANKIEWICZ的其他文献
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{{ truncateString('PAWEL STANKIEWICZ', 18)}}的其他基金
Epigenomic dysfunction at 16q24.1 vascular defects and perinatal consequences
16q24.1 血管缺陷的表观基因组功能障碍和围产期后果
- 批准号:
9922356 - 财政年份:2017
- 资助金额:
$ 79.34万 - 项目类别:
Epigenomic dysfunction at 16q24.1 vascular defects and perinatal consequences
16q24.1 血管缺陷的表观基因组功能障碍和围产期后果
- 批准号:
9287627 - 财政年份:2017
- 资助金额:
$ 79.34万 - 项目类别:
Unrecognized scale and clinical relevance of somatic mosaicism
体细胞嵌合体的规模和临床相关性未被认识
- 批准号:
10011833 - 财政年份:2017
- 资助金额:
$ 79.34万 - 项目类别:
Epigenomic dysfunction at 16q24.1 vascular defects and perinatal consequences
16q24.1 血管缺陷的表观基因组功能障碍和围产期后果
- 批准号:
9767850 - 财政年份:2017
- 资助金额:
$ 79.34万 - 项目类别:
Pathogenetics of the FOX transcription factor gene cluster on 16q24.1
16q24.1 FOX转录因子基因簇的发病机制
- 批准号:
8460859 - 财政年份:2010
- 资助金额:
$ 79.34万 - 项目类别:
Pathogenetics of the FOX transcription factor gene cluster on 16q24.1
16q24.1 FOX转录因子基因簇的发病机制
- 批准号:
7862026 - 财政年份:2010
- 资助金额:
$ 79.34万 - 项目类别:
Pathogenetics of the FOX transcription factor gene cluster on 16q24.1
16q24.1 FOX转录因子基因簇的发病机制
- 批准号:
8259439 - 财政年份:2010
- 资助金额:
$ 79.34万 - 项目类别:
Pathogenetics of the FOX transcription factor gene cluster on 16q24.1
16q24.1 FOX转录因子基因簇的发病机制
- 批准号:
8063912 - 财政年份:2010
- 资助金额:
$ 79.34万 - 项目类别:
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