Epigenomic Modulation of Cystic Fibrosis

囊性纤维化的表观基因组调节

• 批准号: 8435550
• 负责人: William Edward Balch
• 金额: $ 44.74万
• 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 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8435550
• 关键词: Acetylation; Address; Affect; Aging; Animals; Biochemical; Bioinformatics; Biological; Biology; Cardiovascular Diseases; 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; epigenome; 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

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.

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）。