Editing Alveolar Progenitor Cells for Correction of Monogenic Disease
编辑肺泡祖细胞以纠正单基因疾病
基本信息
- 批准号:10417109
- 负责人:
- 金额:$ 124.62万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-23 至 2024-05-31
- 项目状态:已结题
- 来源:
- 关键词:ABCA3 geneAcuteAdultAffectAir PollutionAllelesAlveolarAmniotic FluidBiologicalBirthBostonCRISPR/Cas technologyCell SurvivalCell physiologyCellsCellular biologyChildChildhoodChronicChronic lung diseaseClinicClinicalClinical ResearchClustered Regularly Interspaced Short Palindromic RepeatsCollaborationsCommunitiesComplexDNA sequencingDataDefectDevelopmentDiseaseDisease modelDoctor of MedicineDoctor of PhilosophyEnvironmental Risk FactorEpithelialEpithelial CellsFaceFunctional disorderFutureGenerationsGenesGeneticGenetic DiseasesGoalsGuide RNAHereditary DiseaseHomeostasisHumanIn VitroIndividualInfantInflammationInterstitial Lung DiseasesLaboratoriesLeadLipidsLiposomesLungLung diseasesMediatingMendelian disorderModelingMorbidity - disease rateMusMutationNatural regenerationNeonatalOther GeneticsPathogenesisPathologicPatientsPediatric HospitalsPeripheralPharmacologyPhenotypePreventionProductionProteinsPulmonary FibrosisPulmonary SurfactantsRNARNA deliveryReagentResearchRespiration DisordersRespiratory FailureRespiratory distressRoleRouteSmokingStructureSurfaceSystemTACSTD1 geneTechnologyTelomeraseTestingTransgenic MiceUniversitiesVariantVascular remodelingViralWashingtonWorkairway epitheliumalveolar epitheliumbasecell injurydelivery vehicledesigndirected differentiationdisease-causing mutationeffective therapyepithelial stem cellgene correctiongenetic disorder diagnosishuman modelhuman tissuein vivoinduced pluripotent stem cellinfancylung injurymRNA deliverymembermortalitymouse modelnanoparticleneonatenovel strategiesprogenitorprogramsprototypereagent testingrepairedself-renewalskillsstem cellssuccesssurfactantsurfactant deficiencytraffickingvector
项目摘要
PROJECT SUMMARY
Interstitial Lung Diseases (ILDs), represent a large group of chronic pulmonary disorders that are
common causes of morbidity and mortality of both children and adults worldwide. Alveolar dysfunction,
pulmonary fibrosis, and vascular remodeling associated with chronic ILDs lead to progressive respiratory
failure for which they are few effective therapies. Both genetic and environmental factors underlie the
pathogenesis of ILDs; including smoking, air pollution, and chronic inflammation and genetic disorders.
Mutations in genes regulating surfactant homeostasis or alveolar type 2 (AT2) cell function or survival includes
ABCA3, SFTPB, SFTPC, SFTPA, Telomerase (and related genes) that cause respiratory failure in neonates,
children, and older individuals. Our PCTC Consortium seeks to develop novel strategies designed to use
CRISPR/CAS9 gene editing for lung progenitor cells for correction of a prototypic Childhood Interstitial Lung
Diseases (CHILD) disorder that disrupts pulmonary surfactant homeostasis (ABCA3 deficiency) that leads to
fatal infantile lung disease. Mutations in in the ABCA3 gene disrupts surfactant lipid and protein production
gene causing severe respiratory dysfunction after birth or chronic lung disease in infancy. We will apply
CRISPR/CAS9 mediated gene editing to correct ABCA3 in alveolar progenitor cells as disease targets
applicable to other genetic and acquired disorders affecting AT2 cells and their progenitors. The identification,
targeting and gene editing of alveolar AT2 cells and their progenitors will be widely applicable for the treatment
of both genetic and acquired diseases of the peripheral lung in the future.
项目总结
间质性肺疾病(ILDS)代表一大组慢性肺部疾病,这些疾病
世界各地儿童和成人发病和死亡的常见原因。肺泡功能障碍,
与慢性ILDS相关的肺纤维化和血管重构导致进行性呼吸
对于失败,他们几乎没有有效的治疗方法。遗传和环境因素都是导致
ILDS的发病机制;包括吸烟、空气污染、慢性炎症和遗传疾病。
调节表面活性物质稳态或肺泡2型(AT2)细胞功能或存活的基因突变包括
导致新生儿呼吸衰竭的ABCA3、SFTPB、SFTPC、SFTPA、端粒酶(及相关基因),
儿童和老年人。我们的PCTC联盟寻求开发新的战略,旨在使用
针对肺祖细胞的CRISPR/Cas9基因编辑用于矫正典型的儿童间质肺
疾病(儿童)扰乱肺表面活性物质稳态(ABCA3缺乏症),导致
致命的婴儿肺部疾病。ABCA3基因突变扰乱表面活性物质脂肪和蛋白质的产生
导致出生后严重呼吸功能障碍或婴儿期慢性肺部疾病的基因。我们会申请
CRISPR/Cas9介导的基因编辑纠正作为疾病靶点的肺泡祖细胞中的ABCA3
适用于影响AT2细胞及其祖细胞的其他遗传和获得性疾病。身份证明,
肺泡AT2细胞及其前体细胞的靶向和基因编辑将广泛应用于治疗
未来周围肺的遗传性和获得性疾病。
项目成果
期刊论文数量(24)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
CRISPRi links COVID-19 GWAS loci to LZTFL1 and RAVER1.
- DOI:10.1016/j.ebiom.2021.103806
- 发表时间:2022-01
- 期刊:
- 影响因子:11.1
- 作者:Fink-Baldauf IM;Stuart WD;Brewington JJ;Guo M;Maeda Y
- 通讯作者:Maeda Y
Atf3 defines a population of pulmonary endothelial cells essential for lung regeneration.
ATF3定义了肺部再生必不可少的肺内皮细胞群。
- DOI:10.7554/elife.83835
- 发表时间:2023-05-26
- 期刊:
- 影响因子:7.7
- 作者:Niethamer TK;Levin LI;Morley MP;Babu A;Zhou S;Morrisey EE
- 通讯作者:Morrisey EE
Chromatin and Transcriptional Analysis of Mesoderm Progenitor Cells Identifies HOPX as a Regulator of Primitive Hematopoiesis.
中胚层祖细胞的染色质和转录分析将Hopx鉴定为原始造血的调节剂。
- DOI:10.1016/j.celrep.2017.07.067
- 发表时间:2017-08-15
- 期刊:
- 影响因子:8.8
- 作者:Palpant NJ;Wang Y;Hadland B;Zaunbrecher RJ;Redd M;Jones D;Pabon L;Jain R;Epstein J;Ruzzo WL;Zheng Y;Bernstein I;Margolin A;Murry CE
- 通讯作者:Murry CE
Commentary on the Truncated Splice Variant of the GM-CSF Receptor Beta-Chain in Peripheral Blood Serves as Severity Biomarker of Respiratory Failure in Newborns.
- DOI:10.1159/000514639
- 发表时间:2021
- 期刊:
- 影响因子:2.5
- 作者:Whitsett JA;Jobe AH
- 通讯作者:Jobe AH
The past and future of genetics in pulmonary disease: You can teach an old dog new tricks.
肺部疾病遗传学的过去和未来:你可以教老狗新把戏。
- DOI:10.1002/ppul.24669
- 发表时间:2020
- 期刊:
- 影响因子:3.1
- 作者:Nogee,LawrenceM;Hamvas,Aaron
- 通讯作者:Hamvas,Aaron
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Darrell N. Kotton其他文献
Patient-Specific Inducible Pluripotent Stem Cells Reveal Mechanism of Personalized Therapy for an Inherited Cardiac Arrhythmia
- DOI:
10.1016/j.bpj.2011.11.2947 - 发表时间:
2012-01-31 - 期刊:
- 影响因子:
- 作者:
Kai Wang;Cecile Terrenoire;Kevin J. Sampson;Vivek Lyer;Kelvin W. Chan Tung;Jonathan Lu;Wendy Chung;Robert H. Pass;Gordon Keller;Darrell N. Kotton;Robert S. Kass - 通讯作者:
Robert S. Kass
Derivation of transplantable human thyroid follicular epithelial cells from induced pluripotent stem cells
- DOI:
10.1016/j.stemcr.2024.10.004 - 发表时间:
2024-12-10 - 期刊:
- 影响因子:
- 作者:
Hendrik J. Undeutsch;Alberto Posabella;Andrea B. Alber;Pushpinder S. Bawa;Carlos Villacorta-Martin;Feiya Wang;Laertis Ikonomou;Darrell N. Kotton;Anthony N. Hollenberg - 通讯作者:
Anthony N. Hollenberg
The COPD GWAS gene emADGRG6/em instructs function and injury response in human iPSC-derived type II alveolar epithelial cells
慢性阻塞性肺疾病全基因组关联研究基因 emADGRG6/em 指导人诱导多能干细胞来源的 II 型肺泡上皮细胞的功能和损伤反应
- DOI:
10.1016/j.ajhg.2023.08.017 - 发表时间:
2023-10-05 - 期刊:
- 影响因子:8.100
- 作者:
Rhiannon B. Werder;Kayleigh A. Berthiaume;Carly Merritt;Marissa Gallagher;Carlos Villacorta-Martin;Feiya Wang;Pushpinder Bawa;Vidhi Malik;Shawn M. Lyons;Maria C. Basil;Edward E. Morrisey;Darrell N. Kotton;Xiaobo Zhou;Michael H. Cho;Andrew A. Wilson - 通讯作者:
Andrew A. Wilson
Nascent matrix deposition supports alveolar organoid formation from aggregates in synthetic hydrogels
新生基质沉积有助于在合成水凝胶中由聚集体形成肺泡类器官
- DOI:
10.1016/j.stemcr.2024.11.006 - 发表时间:
2025-01-14 - 期刊:
- 影响因子:5.100
- 作者:
Madeline K. Eiken;Charlie J. Childs;Lindy K. Brastrom;Tristan Frum;Eleanor M. Plaster;Donia W. Ahmed;Ryan C. Spencer;Orren Shachaf;Suzanne Pfeiffer;Justin E. Levine;Konstantinos-Dionysios Alysandratos;Darrell N. Kotton;Jason R. Spence;Claudia Loebel - 通讯作者:
Claudia Loebel
Lung stem cells
- DOI:
10.1007/s00441-007-0479-2 - 发表时间:
2007-09-06 - 期刊:
- 影响因子:2.900
- 作者:
Darrell N. Kotton;Alan Fine - 通讯作者:
Alan Fine
Darrell N. Kotton的其他文献
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{{ truncateString('Darrell N. Kotton', 18)}}的其他基金
Developing a patient-specific organoid model of pulmonary fibrosis using iPSCs
使用 iPSC 开发患者特异性肺纤维化类器官模型
- 批准号:
10026360 - 财政年份:2020
- 资助金额:
$ 124.62万 - 项目类别:
Developing a patient-specific organoid model of pulmonary fibrosis using iPSCs
使用 iPSC 开发患者特异性肺纤维化类器官模型
- 批准号:
10318560 - 财政年份:2020
- 资助金额:
$ 124.62万 - 项目类别:
Developing a patient-specific organoid model of pulmonary fibrosis using iPSCs
使用 iPSC 开发患者特异性肺纤维化类器官模型
- 批准号:
10525231 - 财政年份:2020
- 资助金额:
$ 124.62万 - 项目类别:
Editing Alveolar Progenitor Cells for Correction of Monogenic Disease
编辑肺泡祖细胞以纠正单基因疾病
- 批准号:
10198995 - 财政年份:2016
- 资助金额:
$ 124.62万 - 项目类别:
Epigenenomic and transcriptomic networks in normal and defective lung development
正常和有缺陷的肺发育中的表观基因组和转录组网络
- 批准号:
9144829 - 财政年份:2015
- 资助金额:
$ 124.62万 - 项目类别:
Epigenenomic and transcriptomic networks in normal and defective lung development
正常和有缺陷的肺发育中的表观基因组和转录组网络
- 批准号:
8927909 - 财政年份:2015
- 资助金额:
$ 124.62万 - 项目类别:
Boston University Clinical and Translational Science Institute
波士顿大学临床与转化科学研究所
- 批准号:
9261614 - 财政年份:2015
- 资助金额:
$ 124.62万 - 项目类别:
Boston University Clinical and Translational Science Institute
波士顿大学临床与转化科学研究所
- 批准号:
9126634 - 财政年份:2015
- 资助金额:
$ 124.62万 - 项目类别:
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