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)是美国第三大死因
受香烟烟雾(CS)和遗传倾向的强烈影响。 HHIP,编码 Hedgehog 交互
蛋白质,一直与慢性阻塞性肺病(COPD)的易感性相关,包括气道重塑和
气肿。然而,这种关联背后的分子机制仍然不完全
明白了。我们发表的工作表明,Hhip 杂合小鼠 (Hhip+/-) 重现了多种
COPD 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 Lgr6 的气道平滑肌细胞 (ASMC) 和 Lgr5 中高表达
表达肺泡间充质细胞; COPD ASMC 中的表达减少,显示代谢
从氧化磷酸化转变为与细胞生长增加相关的糖酵解。此外,肺泡
成纤维细胞衍生的 HHIP 促进肺泡类器官共培养中 AT II(肺泡 II 型)细胞的增殖
模型。这些发现表明 Hhip 是 COPD 的关键遗传决定因素,可能调节这两种疾病
通过两个主要肺部互补的内在和外在信号传导来实现气道重塑和肺气肿
间充质细胞类型:ASMC 和肺泡间充质细胞。在当前的提案中,我们的目标是延长
我们之前的研究通过解决与 HHIP 相关的两个机制问题:1)Hhip 缺陷如何影响 HHIP?
ASMC 通过代谢增加气道增厚和细胞增生,从而促进气道重塑
重编程和 2) 肺泡间充质细胞中 Hhip 的缺陷是否以及如何损害了生态位
支持AT II细胞生成。这些问题将通过生化的结合来解决。
分析、谱系追踪、基于 CRISPR 的基因组编辑和类器官共培养模型。在目标 1 中,我们有
确定了 HHIP 和 PKM2(丙酮酸激酶同工酶 M2)之间的新型相互作用,PKM2 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 中的相互作用并确定影响
HHIP 对 CS 诱导气道重塑的影响。在目标 2 中,我们假设髋关节缺陷会导致功能障碍
Lgr5+ 肺泡间充质细胞中的生态位功能对于 AT II 细胞再生非常重要
决定肺气肿的易感性。为了测试这一点,我们选择有条件地耗尽 Lgr5+ 细胞中的 Hhip,
已知的肺泡间充质细胞标记物,然后进行 CS 暴露和随后的测量
空腔大小、Wnt 和 Hedgehog 通路的活性以及两者的增殖和分化
通过目标 2.1 中的互补方法培养肺泡间充质细胞 (Lgr5+) 和 AT II 细胞。在目标 2.2 中,我们
将利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 缺陷小鼠的鼠细胞或通过 CRISPR/Cas-9 编辑的人类原代成纤维细胞
针对 HHIP 的方法。该项目的成功完成将阐明 CS 诱导的分子洞察
COPD 易感性由 HHIP 测定。
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
Deciphering the physiological role and interplay between ubiquitination and phosphorylation pathways to guide targeted cancer therapies
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
- 批准号:
10240580 - 财政年份:2020
- 资助金额:
$ 65.55万 - 项目类别:
Deciphering the physiological role and interplay between ubiquitination and phosphorylation pathways to guide targeted cancer therapies
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
- 批准号:
10663923 - 财政年份:2020
- 资助金额:
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10456316 - 财政年份:2020
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Integrative Characterization on the function of COPD GWAS gene, HHIP
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COPD GWAS 基因 HHIP 功能的综合表征
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