Cystic fibrosis (CF) is a life-limiting genetic disorder affecting 70,000 individuals worldwide (about 30,000 in the US). Recent advances in new drug development – approval of Kalydeco and Orkambi - represent a success for the CF community. However, these compounds are not sufficient to cure CF because (a) they show modest improvement in lung function, a key measure for cystic fibrosis patients; (b) efficacy decreases with long term use; and (c) additional drugs are required in patients with specific CFTR mutations or genes. Additionally, the two approved drugs are cost-intensive (currently $250-300K/year). Thus, the need for new CF pharmacotherapies persists. The context of various CFTR mutations, the complexity of the underlying pathways,
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Hypothesis 2: Systems biology based bioinformatics approaches can accurately identify bioactive small molecules capable of modulating CFTR interactome and CF …show more content…
We will analyze the transcriptomic signatures of small molecules (from LINCS) and CF patients, and CFTR interactome in an integrated manner to identify small molecules that stabilize or inhibit CFTR interactions via its interacting proteins.
Aim 2b will combine prior knowledge of CF-centered biological processes and pathways with CF transcriptomic signatures to construct pathway-specific subnetworks or functional modules. These subnetworks will be used to query LINCS to identify pathway-specific small molecules enabling discovery of therapeutics for systems CF treatment.
Preclinical validation of candidate therapeutics: Experimental validation of candidate therapeutics for CF from Aims 1 and 2 will be performed in collaboration with the Cincinnati Children’s CF Research Center (Naren and Clancy Labs). We will use CF organoid-based models2, 3 to test candidate therapeutics for their effect on fluid secretion. We will also measure the CFTR-dependent short circuit currents (Isc) using polarized primary human airway epithelial cells (both non-CF and CF, and with candidate
Hypothesis 2: Systems biology based bioinformatics approaches can accurately identify bioactive small molecules capable of modulating CFTR interactome and CF …show more content…
We will analyze the transcriptomic signatures of small molecules (from LINCS) and CF patients, and CFTR interactome in an integrated manner to identify small molecules that stabilize or inhibit CFTR interactions via its interacting proteins.
Aim 2b will combine prior knowledge of CF-centered biological processes and pathways with CF transcriptomic signatures to construct pathway-specific subnetworks or functional modules. These subnetworks will be used to query LINCS to identify pathway-specific small molecules enabling discovery of therapeutics for systems CF treatment.
Preclinical validation of candidate therapeutics: Experimental validation of candidate therapeutics for CF from Aims 1 and 2 will be performed in collaboration with the Cincinnati Children’s CF Research Center (Naren and Clancy Labs). We will use CF organoid-based models2, 3 to test candidate therapeutics for their effect on fluid secretion. We will also measure the CFTR-dependent short circuit currents (Isc) using polarized primary human airway epithelial cells (both non-CF and CF, and with candidate