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: 10417109
• 负责人: Darrell N. Kotton
• 金额: $ 124.62万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10417109
• 关键词: ABCA3 gene; Acute; Adult; Affect; Air Pollution; Alleles; Alveolar; Amniotic Fluid; Biological; Birth; Boston; CRISPR/Cas technology; Cell Survival; Cell physiology; Cells; Cellular biology; Child; Childhood; Chronic; Chronic lung disease; Clinic; Clinical; Clinical Research; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Communities; Complex; DNA sequencing; Data; Defect; Development; Disease; Disease model; Doctor of Medicine; Doctor of Philosophy; Environmental Risk Factor; Epithelial; Epithelial Cells; Face; Functional disorder; Future; Generations; Genes; Genetic; Genetic Diseases; Goals; Guide RNA; Hereditary Disease; Homeostasis; Human; In Vitro; Individual; Infant; Inflammation; Interstitial Lung Diseases; Laboratories; Lead; Lipids; Liposomes; Lung; Lung diseases; Mediating; Mendelian disorder; Modeling; Morbidity - disease rate; Mus; Mutation; Natural regeneration; Neonatal; Other Genetics; Pathogenesis; Pathologic; Patients; Pediatric Hospitals; Peripheral; Pharmacology; Phenotype; Prevention; Production; Proteins; Pulmonary Fibrosis; Pulmonary Surfactants; RNA; RNA delivery; Reagent; Research; Respiration Disorders; Respiratory Failure; Respiratory distress; Role; Route; Smoking; Structure; Surface; System; TACSTD1 gene; Technology; Telomerase; Testing; Transgenic Mice; Universities; Variant; Vascular remodeling; Viral; Washington; Work; airway epithelium; alveolar epithelium; base; cell injury; delivery vehicle; design; directed differentiation; disease-causing mutation; effective therapy; epithelial stem cell; gene correction; genetic disorder diagnosis; human model; human tissue; in vivo; induced pluripotent stem cell; infancy; lung injury; mRNA delivery; member; mortality; mouse model; nanoparticle; neonate; novel strategies; progenitor; programs; prototype; reagent testing; repaired; self-renewal; skills; stem cells; success; surfactant; surfactant deficiency; trafficking; vector

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.

项目概要 间质性肺疾病（ILD）代表一大类慢性肺部疾病， 全世界儿童和成人发病和死亡的常见原因。肺泡功能障碍， 肺纤维化和与慢性 ILD 相关的血管重塑导致进行性呼吸系统疾病 对于这种失败，他们几乎没有有效的治疗方法。遗传和环境因素共同作用 ILD 的发病机制；包括吸烟、空气污染、慢性炎症和遗传性疾病。 调节表面活性剂稳态或肺泡 2 型 (AT2) 细胞功能或存活的基因突变包括 ABCA3、SFTPB、SFTPC、SFTPA、端粒酶（及相关基因）导致新生儿呼吸衰竭， 儿童和老年人。我们的 PCTC 联盟致力于开发旨在使用的新颖策略 对肺祖细胞进行 CRISPR/CAS9 基因编辑以校正原型儿童间质性肺 破坏肺表面活性物质稳态（ABCA3 缺乏）的疾病（儿童）疾病，导致 致命的婴儿肺病。 ABCA3 基因突变会破坏表面活性剂脂质和蛋白质的产生 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。我们将申请 CRISPR/CAS9介导的基因编辑纠正肺泡祖细胞中的ABCA3作为疾病靶点 适用于影响 AT2 细胞及其祖细胞的其他遗传性和后天性疾病。身份证明， 肺泡 AT2 细胞及其祖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

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: EBioMedicine
• 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: eLife
• 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: Cell reports
• 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: Neonatology
• 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: Pediatric pulmonology
• 影响因子: 3.1
• 作者: Nogee,LawrenceM;Hamvas,Aaron
• 通讯作者: Hamvas,Aaron