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：
William Edward Balch
金额：
$ 47.48万
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 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7888788
关键词：
Address Affect Aging Animals Biochemical Bioinformatics Biological Biology Cardiovascular system Cell Line Cell Nucleus Cell surface Cells Chemicals Childhood Chloride Channels Chromatin Clinic Collaborations Complementary DNA Cyclic AMP Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Cytosol DNA DNA Modification Process Development Disease Endoplasmic Reticulum Environment Enzymes Epithelial Epithelial Cells Equilibrium Event Failure Gene Expression HDAC7 histone deacetylase Histone Acetylation Histone Deacetylase Histone Deacetylase Inhibitor Histones Homeostasis Human Inherited Intestines Lead Learning Link Longevity Lung Lysosomal Storage Diseases Measures Membrane Membrane Protein Traffic Microarray Analysis Molecular Nerve Degeneration Neurodegenerative Disorders Non-Insulin-Dependent Diabetes Mellitus Pathology Pathway interactions Patients Pharmaceutical Preparations Phenotype Physiology Protein C Inhibitor Proteins Proteome Proteomics Pulmonary Emphysema Recovery Role Signal Pathway Small Interfering RNA Stress System Technology Therapeutic Transcriptional Regulation Transgenes Vorinostat Work clinically relevant disease-causing mutation epigenomics improved inhibitor/antagonist loss of function member mouse model mutant novel premature lungs programs promoter protein folding public health relevance response small molecule tool trafficking

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）是一种遗传性丧失的儿童疾病，蛋白质稳态（Proteeostasis）。 CF主要是由PHE 508缺失在囊性纤维化跨膜电导调节剂（？F508 CFTR）中引起的，这是一种多膜跨度，cAMP调节的氯化物通道。内质网中f508的错误折叠和有效降解，这是外生途径中的第一步，降低了蛋白质的稳定性，导致细胞表面电导，过早的肺衰竭和寿命缩短。 CF是大量错误折叠疾病的成员，包括儿童期肺气肿，溶酶体储存缺陷，II型糖尿病和与衰老相关的神经退行性病理学的疾病。现在，我们证明，通过使用组蛋白脱乙酰基酶（HDAC）抑制剂（HDACI）调节表观基因组，我们可以对肺细胞环境进行重新编程，以实现？f508合成，折叠，降解，降解和运输的速率，导致电导率（功能）在细胞表面上。 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活动调节CFTR折叠，稳定性，运输和功能。（目标2）。公共卫生相关性：囊性纤维化（CF）是一种遗传性的功能丧失儿童疾病，是由囊性纤维化跨膜电导调节剂（？F508 CFTR）突变引起的，这是肺的关键氯化物通道。突变通道的错误折叠和降解导致细胞表面电导，过早肺衰竭和寿命缩短。我们表明，通过调节细胞表观基因组（通过修饰DNA组织控制基因表达的事件），我们可以重新编程肺部细胞环境以纠正疾病，表明通过新型药物对细胞蛋白质组成的药理调节可以对人类失误疾病的纠正产生重大影响。