Twenty years after the discovery of the genetic basis of cystic fibrosis (CF) was identified, we have no new therapies that can restore function to the mutant protein associated with the most common form of the disease. The majority of CF-associated morbidity and mortality arises from progressive pulmonary infection and inflammation. The most common CFTR mutation, ?F508, is present on ~70% of mutant alleles and causes protein misfolding, leading to proteosomal degradation. We discovered a novel microRNA (miRNA)-regulated gene network that influences CFTR transcription and processing, and restores CFTR-?F508 function in airway epithelia. MiR- 138 regulates CFTR expression through its interactions with the transcriptional regulatory protein SIN3A. SIN3A inhibition alters the expression of genes encoding proteins that associate with CFTR and may influence its biosynthesis. Manipulating this regulatory network improves CFTR-?F508 biosynthesis and restores Cl- transport to CF airway epithelia. This proposal leverages our knowledge of the SIN3A-regulated gene network to design new therapies for CF. We will: 1) Identify the key SIN3A-regulated gene products responsible for CFTR-?F508 rescue; 2) Use the genomic signatures of SIN3A-mediated CFTR-?F508 rescue to identify therapeutic agents;and 3) Use lead compounds to rescue CFTR function in newborn pigs with the ?F508 mutation. These complementary strategies should provide new insights into the cellular pathways involved in CFTR biosynthesis and offer new approaches for identifying CFTR-?F508 correctors.
While our knowledge of CFTR function has advanced greatly since the discovery of the gene in 1989; treatments for the disease remain suboptimal and CF remains progressive and fatal. Our discovery of a novel microRNA regulated gene network reveals a previously unrecognized mechanism regulating CFTR expression and biosynthesis; and suggests new approaches for therapeutic interventions. The overall goal of this proposal is to understand the mechanisms by which SIN3A inhibition rescues CFTR- F508 function and translate these insights into therapies for CF.
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