Epigenomic Modulation of Cystic Fibrosis
囊性纤维化的表观基因组调节
基本信息
- 批准号:7888788
- 负责人:
- 金额:$ 47.48万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-04-01 至 2014-02-28
- 项目状态:已结题
- 来源:
- 关键词:AddressAffectAgingAnimalsBiochemicalBioinformaticsBiologicalBiologyCardiovascular systemCell LineCell NucleusCell surfaceCellsChemicalsChildhoodChloride ChannelsChromatinClinicCollaborationsComplementary DNACyclic AMPCystic FibrosisCystic Fibrosis Transmembrane Conductance RegulatorCytosolDNADNA Modification ProcessDevelopmentDiseaseEndoplasmic ReticulumEnvironmentEnzymesEpithelialEpithelial CellsEquilibriumEventFailureGene ExpressionHDAC7 histone deacetylaseHistone AcetylationHistone DeacetylaseHistone Deacetylase InhibitorHistonesHomeostasisHumanInheritedIntestinesLeadLearningLinkLongevityLungLysosomal Storage DiseasesMeasuresMembraneMembrane Protein TrafficMicroarray AnalysisMolecularNerve DegenerationNeurodegenerative DisordersNon-Insulin-Dependent Diabetes MellitusPathologyPathway interactionsPatientsPharmaceutical PreparationsPhenotypePhysiologyProtein C InhibitorProteinsProteomeProteomicsPulmonary EmphysemaRecoveryRoleSignal PathwaySmall Interfering RNAStressSystemTechnologyTherapeuticTranscriptional RegulationTransgenesVorinostatWorkclinically relevantdisease-causing mutationepigenomicsimprovedinhibitor/antagonistloss of functionmembermouse modelmutantnovelpremature lungsprogramspromoterprotein foldingpublic health relevanceresponsesmall moleculetooltrafficking
项目摘要
DESCRIPTION (provided by applicant): Cystic fibrosis (CF) is an inherited loss-of-function childhood disease in protein homeostasis (proteostasis). CF is caused principally by the Phe 508 deletion in the cystic fibrosis transmembrane conductance regulator (?F508 CFTR), a multi-membrane spanning, cAMP-regulated chloride channel. Misfolding and efficient degradation of ?F508 in the endoplasmic reticulum, the first step in the exocytic pathway, reduces the stability of the protein resulting in the loss of cell surface conductance, premature lung failure and shortened lifespan. CF is a member of a large group of misfolding diseases including childhood emphysema, lysosomal storage deficiencies, type II diabetes and neurodegenerative pathologies associated with aging that are defective in proteostasis. We now show that by modulating the epigenome with histone deacetylase (HDAC) inhibitors (HDACi), we can reprogram the lung cell environment to achieve a productive balance between the rate of ?F508 synthesis, folding, degradation and trafficking leading to conductance (function) at the cell surface. This corrective event occurs upon treatment of primary human bronchial epithelial (HBE) cells obtained from ?F homozygous patients (HBE-CF-(?F/?F) with the clinically approved HDACi SAHA to a level of functional cell surface channel activity that is considered corrective for disease. Specific knockdown by small interfering (si)-RNA of HDAC7 results in recovery of conductance in lung cells, suggesting that only a subset of HDAC activities modulates CFTR folding, stability, trafficking and function. We suggest that HVACs control a transcriptional program that is linked to proteostasis to achieve folding, stability, trafficking and function of ?F508 that can be protective for CF. In this proposal, we propose to develop specific small molecules to inhibit HDAC7 function (Aim 1) and to explore the role of HDAC7 in CF biology (Aim 2). Use of HDACi to chemically modulate linked transcriptional and protein homeostasis environments is anticipated to have high impact on correction of human misfolding disease.
PUBLIC HEALTH RELEVANCE: Cystic fibrosis (CF) is an inherited loss-of-function childhood disease caused by mutation of the cystic fibrosis transmembrane conductance regulator (?F508 CFTR), a critical chloride channel in the lung. Misfolding and degradation of the mutant channel results in the loss of cell surface conductance, premature lung failure and shortened lifespan. We show that by modulating the cellular epigenome (events that control gene expression in the nucleus through modification of DNA organization), we can reprogram the lung cell environment to correct disease, demonstrating that pharmacological modulation of the protein composition of the cell through a novel group of drugs can have a high impact on correction of human misfolding disease.
描述(由申请人提供):囊性纤维化(CF)是一种遗传性的蛋白质稳态(蛋白质稳态)功能丧失的儿童疾病。 CF 主要是由囊性纤维化跨膜电导调节因子 (?F508 CFTR) 中的 Phe 508 缺失引起,囊性纤维化跨膜电导调节因子是一种跨膜、cAMP 调节的氯离子通道。内质网中 ?F508 的错误折叠和有效降解(胞吐途径的第一步)降低了蛋白质的稳定性,导致细胞表面电导丧失、过早肺衰竭和寿命缩短。 CF 是一大类错误折叠疾病的一员,包括儿童肺气肿、溶酶体储存缺陷、II 型糖尿病和与衰老相关的蛋白质稳态缺陷的神经退行性疾病。我们现在表明,通过用组蛋白脱乙酰酶 (HDAC) 抑制剂 (HDACi) 调节表观基因组,我们可以重新编程肺细胞环境,以实现 ?F508 合成、折叠、降解和运输速率之间的有效平衡,从而导致细胞表面的电导(功能)。这种纠正事件发生在用临床批准的 HDACi SAHA 治疗从 ?F 纯合子患者 (HBE-CF-(?F/?F) 获得的原代人支气管上皮 (HBE) 细胞至被认为可纠正疾病的功能性细胞表面通道活性水平时。HDAC7 的小干扰 (si)-RNA 的特异性敲低导致肺细胞电导恢复,这表明只有一部分 HDAC 活性调节 CFTR 折叠、稳定性、运输和功能。我们认为 HVAC 控制与蛋白质稳态相关的转录程序,以实现可保护 CF 的 ?F508 的折叠、稳定性、运输和功能。在该提案中,我们建议开发特定的小分子来抑制HDAC7功能(目标1)并探索HDAC7在CF生物学中的作用 (目标 2)。使用 HDACi 以化学方式调节相关转录和蛋白质稳态环境预计将对纠正人类错误折叠疾病产生重大影响。
公共健康相关性:囊性纤维化 (CF) 是一种遗传性儿童功能丧失性疾病,由囊性纤维化跨膜电导调节因子 (?F508 CFTR) 突变引起,囊性纤维化跨膜电导调节因子是肺部的关键氯离子通道。突变通道的错误折叠和降解会导致细胞表面电导丧失、过早肺衰竭和寿命缩短。我们证明,通过调节细胞表观基因组(通过修改 DNA 组织来控制细胞核中基因表达的事件),我们可以重新编程肺细胞环境以纠正疾病,这证明通过一组新型药物对细胞蛋白质组成的药理调节可以对纠正人类错误折叠疾病产生重大影响。
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 }}
William Edward Balch其他文献
William Edward Balch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('William Edward Balch', 18)}}的其他基金
Applying Spatial Covariance to Understand Human Variation in Genetic Disease
应用空间协方差来了解遗传疾病的人类变异
- 批准号:
10734426 - 财政年份:2023
- 资助金额:
$ 47.48万 - 项目类别:
Using Genetic Diversity to Manage Neurological Disease
利用遗传多样性来治疗神经系统疾病
- 批准号:
10538562 - 财政年份:2021
- 资助金额:
$ 47.48万 - 项目类别:
Using Genetic Diversity to Manage Neurological Disease
利用遗传多样性来治疗神经系统疾病
- 批准号:
10321554 - 财政年份:2021
- 资助金额:
$ 47.48万 - 项目类别:
Using Genetic Diversity to Manage Neurological Disease
利用遗传多样性来治疗神经系统疾病
- 批准号:
10706236 - 财政年份:2021
- 资助金额:
$ 47.48万 - 项目类别:
Modulation of Lung Disease by Genetic/Epigenetic Profiling
通过遗传/表观遗传分析调节肺部疾病
- 批准号:
10369651 - 财政年份:2010
- 资助金额:
$ 47.48万 - 项目类别:
相似海外基金
Hormone therapy, age of menopause, previous parity, and APOE genotype affect cognition in aging humans.
激素治疗、绝经年龄、既往产次和 APOE 基因型会影响老年人的认知。
- 批准号:
495182 - 财政年份:2023
- 资助金额:
$ 47.48万 - 项目类别:
Parkinson's disease and aging affect neural activation during continuous gait alterations to the split-belt treadmill: An [18F] FDG PET Study.
帕金森病和衰老会影响分体带跑步机连续步态改变期间的神经激活:[18F] FDG PET 研究。
- 批准号:
400097 - 财政年份:2019
- 资助金额:
$ 47.48万 - 项目类别:
The elucidation of the mechanism by which intestinal epithelial cells affect impaired glucose tolerance during aging
阐明衰老过程中肠上皮细胞影响糖耐量受损的机制
- 批准号:
19K09017 - 财政年份:2019
- 资助金额:
$ 47.48万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Does aging of osteocytes adversely affect bone metabolism?
骨细胞老化会对骨代谢产生不利影响吗?
- 批准号:
18K09531 - 财政年份:2018
- 资助金额:
$ 47.48万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Links between affect, executive function, and prefrontal structure in aging: A longitudinal analysis
衰老过程中情感、执行功能和前额叶结构之间的联系:纵向分析
- 批准号:
9766994 - 财政年份:2018
- 资助金额:
$ 47.48万 - 项目类别:
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
- 批准号:
9320090 - 财政年份:2017
- 资助金额:
$ 47.48万 - 项目类别:
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
- 批准号:
10166936 - 财政年份:2017
- 资助金额:
$ 47.48万 - 项目类别:
Affect regulation and Beta Amyloid: Maturational Factors in Aging and Age-Related Pathology
影响调节和 β 淀粉样蛋白:衰老和年龄相关病理学中的成熟因素
- 批准号:
9761593 - 财政年份:2017
- 资助金额:
$ 47.48万 - 项目类别:
Experimental Model of Depression in Aging: Insomnia, Inflammation, and Affect Mechanisms
衰老过程中抑郁症的实验模型:失眠、炎症和影响机制
- 批准号:
9925164 - 财政年份:2016
- 资助金额:
$ 47.48万 - 项目类别:
Experimental Model of Depression in Aging: Insomnia, Inflammation, and Affect Mechanisms
衰老过程中抑郁症的实验模型:失眠、炎症和影响机制
- 批准号:
9345997 - 财政年份:2016
- 资助金额:
$ 47.48万 - 项目类别:














{{item.name}}会员




