Epigenomic Modulation of Cystic Fibrosis

囊性纤维化的表观基因组调节

• 批准号: 8761533
• 负责人: William Edward Balch
• 金额: $ 47.38万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8761533
• 关键词: Acetylation; Address; Affect; Biochemical; Biological; Biology; Bromodomain; Cell physiology; Cell surface; Cells; Chemicals; Childhood; Chloride Channels; Chronic; Clinic; Cyclic AMP; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Deacetylation; Development; Disease; Ensure; Environment; Equilibrium; Evolution; Failure; Foundations; Funding; Genome; Goals; Health; Histone Deacetylase; Individual; Inherited; Learning; Link; Longevity; Manuscripts; Membrane; Molecular; Mutation; Pathway interactions; Preparation; Progress Reports; Protein Acetylation; Protein Family; Proteins; Proteome; Publications; Reader; Role; Signal Pathway; Stress; Therapeutic; Variant; Work; cell type; clinically relevant; epigenomics; fitness; functional restoration; histone acetyltransferase; infancy; insight; loss of function; mutant; premature lungs; programs; protein folding; protein function; response; trafficking; transcription factor

DESCRIPTION (provided by applicant): This competitive renewal retains its specific focus on the role of histone deacetylase (HDAC) activity in cystic fibrosis (CF), building on our substantia progress in the last funding period (2010 to 2014). CF is an inherited loss-of-function disease caused principally by a Phe508 deletion in the cystic fibrosis transmembrane conductance regulator (CFTR), referred to as F508del. We are now beginning to appreciate the importance of many other mutations in providing insights into synthesis, folding, trafficking and stability/function pathways that will be addressed in this competitive renewal focused on the deacetylation ('eraser') biology of HDAC7 in correcting F508del. CFTR is a multi-membrane spanning, cAMP-regulated chloride channel. Misfolding of F508del, and likely many other mutants, reduce the synthesis, folding, trafficking and/or stability/function of CFTR resulting in the loss of cell surface conductance, premature lung failure and shortened lifespan. As such, CF is a disease of proteostasis biology as we have demonstrated under auspices of the previous funding period and in the past. Proteostasis is the cellular environment that maintains the proteome for normal cellular function. It is frequently adjusted using multiple signaling pathways to protect the cell from protein folding stress during transient insult and in response to inherite, chronic misfolding diseases. The thrust of this competitive renewal is to seek correction of CF through an understanding HDAC7 deacetylation function. During the last funding period we provided evidence that HDACs, particularly HDAC7, can exert control through multiple avenues- transcriptional, translational and/or co-/post-translational programs that are linked to different components of the proteome through acetylation/deacetylation pathways. These can operate together to achieve a level of stability and function of F508del that can be protective and corrective for CF. Herein, we propose to focus on the enabling working hypothesis that the stability and function of wild-type (WT) and F508del CFTR is strongly influenced by the HDAC7 network of deacetylation activities that operate through transcriptional, translational and/or co-/post-translational mechanisms to direct protein function, and that the HDAC7 specific network can be manipulated to provide a protective environment for CF in the clinic. To explore our working hypothesis, we propose two aims: Aim 1 focuses on understanding the role of new targets revealed by the HDAC7 interactome generated during the last funding period that are likely responsible for HDAC7 function in correction of CF; Aim 2 focuses on approaches to understand the role of HDAC7 in (re)balancing acetylation-deacetylation pathways involved in correcting CF variants. The combined Aims will provide systematic approach to address HDAC7 regulated pathways affecting F508del synthesis, folding, trafficking and stability/function at the cell surface. They will provide an in-depth link to the cyclical acetylation- deacetylation environments regulated by HDAC7 that may be corrective for CF disease in the clinic

描述(由申请人提供)：本次竞争性续签保持了对组蛋白脱乙酰酶(HDAC)活性在囊性纤维化(CF)中的作用的具体关注，建立在我们在上一个资助期(2010至2014)的实质性进展的基础上。Cf是一种遗传性功能丧失疾病，主要由囊性纤维化跨膜电导调节因子(CFTR)Phe508缺失引起，称为F508del。我们现在开始认识到许多其他突变的重要性，这些突变在提供对合成、折叠、运输和稳定/功能途径的见解方面具有重要意义，这些途径将在这一竞争性更新中得到解决，重点是HDAC7在纠正F508del中的脱乙酰基(‘橡皮’)生物学。Cftr是一种多膜跨膜、cAMP调节的氯离子通道。F508del的错误折叠，以及可能许多其他突变体，降低了CFTR的合成、折叠、运输和/或稳定性/功能，导致细胞表面电导丧失，早产肺衰竭和寿命缩短。因此，CF是一种蛋白代谢生物学疾病，正如我们在前一个资助期和过去所证明的那样。蛋白质平衡是维持蛋白质组正常细胞功能的细胞环境。它经常使用多种信号通路进行调节，以保护细胞在短暂的损伤和遗传性的慢性错误折叠疾病中免受蛋白质折叠压力的影响。这一竞争性更新的主旨是通过了解HDAC7的去乙酰化功能来寻求纠正CF。在上一次资助期间，我们提供的证据表明，HDACs，特别是HDAC7，可以通过多种途径发挥控制作用-转录、翻译和/或共/翻译后程序，这些程序通过乙酰化/去乙酰化途径与蛋白质组的不同成分相连。这些都可以共同运行，以实现F508del的稳定性和功能，对CF具有保护和纠正作用。在这里，我们建议重点关注使能工作假设，即野生型(WT)和F508del CFTR的稳定性和功能受到HDAC7去乙酰化活性网络的强烈影响，该网络通过转录、翻译和/或协同/翻译后机制来指导蛋白质功能，并且HDAC7特异性网络可以被操纵以在临床上为CF提供保护环境。为了探索我们的工作假说，我们提出了两个目标：目标1专注于了解在最后一个资金来源期间产生的HDAC7互动组所揭示的新靶点的作用，这些靶可能负责HDAC7在纠正CF的功能中的作用；目的2专注于了解HDAC7在纠正CF变体所涉及的(重新)平衡乙酰化-去乙酰化途径中的作用的方法。联合的AIMS将提供系统的方法来解决HDAC7调节的影响F508del的合成、折叠、运输和细胞表面的稳定性/功能的途径。它们将提供与HDAC7调节的周期性乙酰化-去乙酰化环境的深入联系，这可能是临床上纠正CF病的方法