Integrative Characterization on the function of COPD GWAS gene, HHIP
COPD GWAS 基因 HHIP 功能的综合表征
基本信息
- 批准号:10598541
- 负责人:
- 金额:$ 65.55万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-04-05 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:3-DimensionalAddressAgonistAirway FibrosisAlveolarAlveolusBindingBiochemicalBiologicalBiological AssayCRISPR/Cas technologyCause of DeathCell Differentiation processCell ProliferationCellsChromatinChronicChronic Obstructive Pulmonary DiseaseCigarette smoke-induced emphysemaClustered Regularly Interspaced Short Palindromic RepeatsCoculture TechniquesCollagenCommunicationDataDepositionDevelopmentDifferentiation and GrowthDisease susceptibilityDistalEnzymesEpithelial CellsErinaceidaeFibroblastsFoundationsGeneral PopulationGenerationsGenesGenetic DeterminismGenetic Predisposition to DiseaseGenotypeGlycolysisGrowthHeterozygoteHumanHyperplasiaImpairmentIn VitroInvestigationIsoenzymesLGR5 geneLungMeasurementMediatingMesenchymalMetabolicMethodsModelingMolecularMusOrganoidsOxidative PhosphorylationOxygen ConsumptionPathologicPathway interactionsPatientsPredispositionProliferatingProtein DeficiencyProtein Kinase InteractionProteinsPublic HealthPublishingPulmonary EmphysemaPyruvate KinaseRoleSHH geneSignal TransductionSmokeSmooth Muscle MyocytesSortingTestingType II Epithelial Receptor CellWorkaerobic glycolysisage relatedaging populationairway obstructionairway remodelingalveolar type II cellcell growthcell regenerationcell typecigarette smokecigarette smoke-inducedcigarette smoke-induced COPDcigarette smokingdisease phenotypeexposure to cigarette smokegenome editinggenome wide association studyin vivoinhibitorinsightmutantnovelpersonalized medicinepreventprotein expressionpulmonary functionpyruvate kinase deficiencyrespiratory smooth musclerisk variantsingle-cell RNA sequencingstem cellstargeted treatment
项目摘要
Chronic obstructive pulmonary disease (COPD), ranks as the third leading cause of death in the U.S. It is also
strongly influenced by cigarette smoke (CS) and genetic predisposition. HHIP, encoding Hedgehog interacting
protein, has consistently been associated with the susceptibility to COPD including airway remodeling and
emphysema. However, the molecular mechanism underlying this association remains incompletely
understood. Our published work has demonstrated that Hhip heterozygous mice (Hhip+/-) recapitulated multiple
COPD pathological features including smoke- and age-related emphysema and airway remodeling. We also
found that HHIP is highly expressed in Lgr6-expressing airway smooth muscle cells (ASMCs) and Lgr5-
expressing alveolar mesenchymal cells; has reduced expression in COPD ASMCs that display a metabolic
shift from oxidative phosphorylation to glycolysis associated with increased cell growth. Furthermore, alveolar
fibroblasts-derived HHIP promotes proliferation of AT II (alveolar type II) cells in alveolar organoid co-culture
model. These findings suggested that Hhip, the key genetic determinant for COPD, possibly modulates both
airway remodeling and emphysema through complementarily intrinsic and extrinsic signaling in two major lung
mesenchymal cell types: ASMCs and alveolar mesenchymal cells. In this current proposal, we aim to extend
our previous studies by addressing two mechanistic questions related with HHIP: 1) How deficiency of Hhip in
ASMCs promote airway remodeling by increasing airway thickening and cell hyperplasia through metabolic
reprograming and 2) whether and how deficiency of Hhip in alveolar mesenchymal cells have impaired niche to
support AT II cell generation. These questions will be addressed through the combinations of biochemical
assays, lineage tracing, CRISPR-based genome editing and organoid co-culture models. In Aim1, we have
identified a novel interaction between HHIP and PKM2 (pyruvate kinase isozyme M2), a rate-limiting enzyme in
the last step for glycolysis. We will further characterize their interaction in AMSCs as well as determine impacts
of HHIP on CS-induced airway remodeling. In Aim 2, we hypothesize that Hhip deficiency leads to impaired
niche function in Lgr5+ alveolar mesenchymal cells that are important for AT II cells regeneration thereby
determines emphysema susceptibility. To test this, we choose to conditionally deplete Hhip in Lgr5+ cells, a
known alveolar mesenchymal cells marker followed by CS exposure and subsequent measurements on
airspace size, the activity of the Wnt and Hedgehog pathway and proliferation and differentiation of both
alveolar mesenchymal cells (Lgr5+) and AT II cells by complementary approaches in Aim 2.1. In Aim 2.2., we
will use alveolar organoid co-culture model to dissect the mechanism by which Hhip determines niche function
using either murine cells from Hhip deficient mice or from human primary fibroblasts edited by CRISPR/Cas-9
method targeting HHIP. Successful completion of this project will illuminate molecular insights into CS-induced
COPD susceptibility determined by HHIP.
慢性阻塞性肺疾病(COPD)是美国第三大死亡原因。
受吸烟(CS)和遗传易感性的强烈影响。HHIP,编码Hedgehog相互作用
蛋白质,一直与COPD的易感性相关,包括气道重塑和
肺气肿然而,这种关联的分子机制仍然不完全
明白我们已发表的工作表明,Hhip杂合子小鼠(Hhip+/-)重演了多个
COPD的病理特征包括吸烟和年龄相关的肺气肿和气道重塑。我们也
发现HHIP在表达Lgr 6的气道平滑肌细胞(ASMC)中高度表达,而Lgr 5-
表达肺泡间充质细胞;在COPD ASMC中表达减少,
从氧化磷酸化转变为糖酵解,与细胞生长增加有关。此外,肺泡
成纤维细胞衍生的HHIP促进肺泡类器官共培养物中AT II(肺泡II型)细胞的增殖
模型这些发现表明,Hip,COPD的关键遗传决定因素,可能调节两者
通过两个主要肺组织中互补的内源性和外源性信号传导,
间充质细胞类型:ASMCs和肺泡间充质细胞。在目前的提案中,我们的目标是扩大
我们以前的研究通过解决与HHIP相关的两个机制问题:1)HHIP缺乏如何在
ASMCs通过代谢增加气道增厚和细胞增生促进气道重塑
2)肺泡间充质细胞中Hhip的缺乏是否以及如何损害了微生态位,
支持AT II细胞生成。这些问题将通过生物化学和生物化学的结合来解决。
分析、谱系追踪、基于CRISPR的基因组编辑和类器官共培养模型。在AIM 1中,我们有
确定了HHIP和PKM 2(丙酮酸激酶同工酶M2)之间的一种新的相互作用,PKM 2是一种限速酶,
糖酵解的最后一步我们将进一步描述它们在AMSC中的相互作用,
HHIP对CS诱导的气道重塑的影响。在目标2中,我们假设Hip缺乏导致受损的
Lgr 5+肺泡间充质细胞的生态位功能对AT II细胞再生很重要,
决定了肺气肿的易感性。为了测试这一点,我们选择在Lgr 5+细胞中有条件地消耗Hip,
已知的肺泡间充质细胞标记物,随后暴露于CS,
空域大小、Wnt和Hedgehog通路的活性以及两者的增殖和分化
肺泡间充质细胞(Lgr 5+)和AT II细胞的互补方法在目的2.1。在Aim 2.2中,我们
将使用肺泡类器官共培养模型来剖析Hhip决定生态位功能的机制
使用来自Hhip缺陷小鼠或来自通过CRISPR/Cas-9编辑的人原代成纤维细胞的鼠细胞
方法针对HHIP。该项目的成功完成将阐明CS诱导的分子见解
通过HHIP确定COPD易感性。
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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Wenyi Wei其他文献
Wenyi Wei的其他文献
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{{ truncateString('Wenyi Wei', 18)}}的其他基金
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破译泛素化和磷酸化途径之间的生理作用和相互作用,以指导靶向癌症治疗
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10240580 - 财政年份:2020
- 资助金额:
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Deciphering the physiological role and interplay between ubiquitination and phosphorylation pathways to guide targeted cancer therapies
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Integrative Characterization on the function of COPD GWAS gene, HHIP
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