Molecular Therapies for Cystic Fibrosis Lung Disease
囊性纤维化肺病的分子疗法
基本信息
- 批准号:10470331
- 负责人:
- 金额:$ 231.16万
- 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:2020-09-01 至 2025-07-31
- 项目状态:未结题
- 来源:
- 关键词:AddressAdenineAirway DiseaseAmphotericin BAnimal ModelAnionsApicalBacteriaBicarbonatesBiologyCellsClinical ResearchClustered Regularly Interspaced Short Palindromic RepeatsComplementCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorDNADataDeaminaseDefectDevelopmentDiseaseEpithelial CellsFamily suidaeFerretsFormulationGenetic DiseasesGenetic EngineeringGoalsGuide RNAHost DefenseHumanIn VitroInfrastructureIon ChannelKnowledgeLifeLungLung diseasesMediatingMissense MutationModelingMolecularMorbidity - disease rateMucociliary ClearanceMutationNatural ImmunityNebulizerNucleotidesPathogenesisPeptidesPersonsPreventionPropertyProteinsPulmonary Cystic FibrosisRNA SplicingRecordsResearchResearch PersonnelRespiratory FailureRibonucleoproteinsRoleServicesSiteSurfaceTechniquesTestingVariantWorkadeno-associated viral vectorairway epitheliumairway obstructionairway surface liquidantimicrobialbase editingbase editorcell typecellular targetingcystic fibrosis airwaycystic fibrosis airway epitheliagain of functiongene discoverygene repairgene replacementgene therapyin vivoinnovationloss of functionmortalitynovel therapeutic interventionnovel therapeuticsnull mutationoverexpressionpreventprogenitorprogramsprotein functionrecurrent infectionrepairedsmall moleculetool
项目摘要
OVERALL COMPONENT
PROJECT SUMMARY
Cystic fibrosis (CF) is a common life-shortening genetic disease that causes progressive lung failure due
to recurrent infections and airway obstruction. While our knowledge of CFTR function has advanced
greatly in the 30 years since the discovery of the gene, treatments for the disease remain suboptimal and
CF remains progressive and fatal. Advances with small molecule CFTR modulator therapies have
helped restore protein function for many mutations, but approximately 10% of people with CF have not
benefited from these strategies, including people with nonsense and splicing mutations. The central
theme of this proposal is developing new molecular therapies to prevent or treat CF lung disease.
The goal of our three projects and four cores is to exploit the power of our in vitro and animal models to
address questions fundamental to lung disease pathogenesis and to use this knowledge to inform new
therapeutic strategies to complement CF defects, including gene repair and the addition of a small
molecule that forms anion channels. The three closely interrelated Projects will work together to
accomplish the following goals: 1) To restore CFTR function using targeted single nucleotide
editing. We hypothesize that cells in the surface airway epithelium, including those with progenitor
capacity, can be targeted to repair CFTR mutations using base editing. 2) To understand the
mechanisms of amphotericin B (AmB)-induced anion secretion in airway epithelia and to test the
hypothesis that AmB can restore CF host defenses in vivo. AmB is a small molecule that forms
anion channels. 3) To determine how CFTR expression in pulmonary ionocytes and ciliated cells
regulates properties of the airway surface liquid that are crucial for clearance and innate
immunity. The development of effective gene therapies for cystic fibrosis lung disease must be guided
by a clear understanding of pathophysiologic mechanisms of disease and the relevant cellular targets for
CFTR gene replacement or editing.
The Project Leaders and their teams have outstanding track records of collaborative CF research, and
here they sharpen their focus to a common goal. Their highly creative research is supported by four
cores that provide innovative infrastructure and services. Through these studies we hope to accelerate
the development of new therapeutics for CF lung disease.
!
总体组件
项目摘要
囊性纤维化(CF)是一种常见的缩短寿命的遗传性疾病,由于其在肺组织中的分布而导致进行性肺衰竭。
复发性感染和气道阻塞虽然我们对CFTR功能的了解有所提高,
在基因发现后的30年里,对这种疾病的治疗仍然不是最理想的,
CF仍然是进行性和致命的。小分子CFTR调节剂疗法的进展
有助于恢复许多突变的蛋白质功能,但大约10%的CF患者没有
受益于这些策略,包括无意义和剪接突变的人。中央
该提案的主题是开发新的分子疗法来预防或治疗CF肺病。
我们的三个项目和四个核心的目标是利用我们的体外和动物模型的力量,
解决肺部疾病发病机制的基本问题,并利用这些知识为新的
治疗策略,以弥补CF缺陷,包括基因修复和增加一个小的
形成阴离子通道的分子。这三个密切相关的项目将共同努力,
实现以下目标:1)使用靶向的单核苷酸恢复CFTR功能
编辑.我们假设,在表面气道上皮细胞,包括那些祖细胞,
能力,可以使用碱基编辑靶向修复CFTR突变。2)了解
目的:探讨氨蝶呤B(AmB)诱导气道上皮细胞阴离子分泌的机制,并检测其对气道上皮细胞阴离子分泌的影响。
AmB可以在体内恢复CF宿主防御的假设。AmB是一种小分子,
阴离子通道3)为了确定CFTR在肺离子细胞和纤毛细胞中的表达,
调节气道表面液体的性质,这些性质对于清除和先天性
免疫力必须指导囊性纤维化肺病有效基因疗法的开发
通过对疾病的病理生理机制和相关细胞靶点的清楚理解,
CFTR基因替换或编辑。
项目负责人和他们的团队在CF合作研究方面有着出色的记录,
在这里,他们把注意力集中在一个共同目标上。他们极具创造性的研究得到了四个
提供创新基础设施和服务的核心。通过这些研究,我们希望加快
CF肺病新疗法的开发。
!
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
PAUL B MCCRAY其他文献
PAUL B MCCRAY的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('PAUL B MCCRAY', 18)}}的其他基金
Molecular Therapies for Cystic Fibrosis Lung Disease
囊性纤维化肺病的分子疗法
- 批准号:
10677580 - 财政年份:2020
- 资助金额:
$ 231.16万 - 项目类别:
Gene Editing Strategies to Correct CFTR Mutations
纠正 CFTR 突变的基因编辑策略
- 批准号:
10024666 - 财政年份:2020
- 资助金额:
$ 231.16万 - 项目类别:
Gene Editing Strategies to Correct CFTR Mutations
纠正 CFTR 突变的基因编辑策略
- 批准号:
10677600 - 财政年份:2020
- 资助金额:
$ 231.16万 - 项目类别:
Molecular Therapies for Cystic Fibrosis Lung Disease
囊性纤维化肺病的分子疗法
- 批准号:
10024661 - 财政年份:2020
- 资助金额:
$ 231.16万 - 项目类别:
相似海外基金
The Role of Adenine Nucleotide Translocase in Mitochondrial Dysfunction Associated Senescence in Chronic Obstructive Pulmonary Disease (COPD)
腺嘌呤核苷酸转位酶在慢性阻塞性肺病(COPD)线粒体功能相关衰老中的作用
- 批准号:
10633608 - 财政年份:2023
- 资助金额:
$ 231.16万 - 项目类别:
Pathways of Succinate Accumulation and Adenine Nucleotide Depletion in Cardiac Ischemia
心脏缺血中琥珀酸积累和腺嘌呤核苷酸消耗的途径
- 批准号:
10534031 - 财政年份:2022
- 资助金额:
$ 231.16万 - 项目类别:
Pathways of Succinate Accumulation and Adenine Nucleotide Depletion in Cardiac Ischemia
心脏缺血中琥珀酸积累和腺嘌呤核苷酸消耗的途径
- 批准号:
10794933 - 财政年份:2022
- 资助金额:
$ 231.16万 - 项目类别:
Development of nobel assay methods for miRNA and adenine methyltransferase using FRET
使用 FRET 开发 miRNA 和腺嘌呤甲基转移酶的诺贝尔检测方法
- 批准号:
21K05120 - 财政年份:2021
- 资助金额:
$ 231.16万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Critical assessment of DNA adenine methylation in brain cells from healthy aging and Alzheimer's disease
健康老龄化和阿尔茨海默病脑细胞 DNA 腺嘌呤甲基化的批判性评估
- 批准号:
10365337 - 财政年份:2021
- 资助金额:
$ 231.16万 - 项目类别:
DNA Methylation at N6-Adenine in Placental Trophoblast Development
胎盘滋养层发育中 N6-腺嘌呤 DNA 甲基化
- 批准号:
10033546 - 财政年份:2020
- 资助金额:
$ 231.16万 - 项目类别:
DNA Methylation at N6-Adenine in Placental Trophoblast Development
胎盘滋养层发育中 N6-腺嘌呤 DNA 甲基化
- 批准号:
10613902 - 财政年份:2020
- 资助金额:
$ 231.16万 - 项目类别:
DNA Methylation at N6-Adenine in Placental Trophoblast Development
胎盘滋养层发育中 N6-腺嘌呤 DNA 甲基化
- 批准号:
10396102 - 财政年份:2020
- 资助金额:
$ 231.16万 - 项目类别:
DNA Methylation at N6-Adenine in Placental Trophoblast Development
胎盘滋养层发育中 N6-腺嘌呤 DNA 甲基化
- 批准号:
10226235 - 财政年份:2020
- 资助金额:
$ 231.16万 - 项目类别:
DNA Methylation at N6-Adenine in Placental Trophoblast Development
胎盘滋养层发育中 N6-腺嘌呤 DNA 甲基化
- 批准号:
10705982 - 财政年份:2020
- 资助金额:
$ 231.16万 - 项目类别: