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.