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：
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
项目类别：
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

项目摘要

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）：本次竞争性更新保留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，以我们在上一个资助期（2010 年至 2014 年）的实质性进展为基础。 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）中的Phe508缺失（称为F508del）引起。我们现在开始认识到许多其他突变在提供对合成、折叠、运输和稳定性/功能途径的见解方面的重要性，这些突变将在本次竞争性更新中得到解决，重点关注 HDAC7 的脱乙酰化（“擦除器”）生物学以纠正 F508del。 CFTR 是一种跨膜、cAMP 调节的氯离子通道。 F508del 的错误折叠以及可能的许多其他突变体会减少 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、过早肺衰竭和寿命缩短。因此，正如我们在上一个资助期和过去的资助下所证明的那样，CF 是一种蛋白质稳态生物学疾病。蛋白质稳态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传导途径进行调整，以保护细胞在短暂损伤期间免受蛋白质折叠应激以及响应遗传性慢性错误折叠疾病。这一竞争性更新的主旨是通过了解 HDAC7 脱乙酰化功能来寻求 CF 的校正。在上一个资助期间，我们提供的证据表明，HDAC，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/脱乙酰化途径与蛋白质组的不同成分相关联。这些可以一起运行以实现 F508del 的一定程度的稳定性和功能，从而保护和纠正 CF。在此，我们建议重点关注以下可行的工作假设：野生型 (WT) 和 F508del CFTR 的稳定性和功能受到 HDAC7 脱乙酰化活性网络的强烈影响，该网络通过转录、翻译和/或共/后-指导蛋白质功能的翻译机制，并且可以操纵 HDAC7 特定网络为临床上 CF 提供保护环境。为了探索我们的工作假设，我们提出了两个目标：目标 1 侧重于了解上一个资助期间生成的 HDAC7 相互作用组所揭示的新靶标的作用，这些新靶标可能负责 HDAC7 在 CF 校正中的功能；目标 2 重点关注了解 HDAC7 在（重新）平衡乙酰化-脱乙酰化途径（涉及纠正 CF 变异）中的作用的方法。合并后的目标将提供系统方法来解决影响细胞表面 F508del 合成、折叠、运输和稳定性/功能的 HDAC7 调节途径。它们将提供与 HDAC7 调节的周期性乙酰化-脱乙酰化环境的深入联系，这可能在临床上纠正 CF 疾病