For CFTR biogenesis, our interest lies in understanding how CFTR is folded during translation. Our recent work (PMID: 39641142) suggests that the Endoplasmic Reticulum (ER) membrane protein complex (EMC) plays a critical in both the production and function of CFTR. However, the mechanism by which EMC facilitate CFTR biosynthesis remains largely unknown.
In terms of CFTR degradation, the focus is on how ER luminal factors facilitate the degradation of misfolded CFTR through the ER-associated degradation (ERAD) pathway. Previously, we discovered that inhibiting the ER luminal co-chaperone DNAJB9 can enhance the expression and function of ΔF508-CFTR, the most common mutation in CF (PMID: 31285458). Currently, we are in the process of identifying other ER luminal proteins that may work in conjunction with DNAJB9 to aid the degradation of misfolded CFTR.
Additionally, research is being conducted on targeting CF caused by premature termination codons (PTCs) using suppressor transfer RNA (sup-tRNA) technology. Our recent study (PMID: 40539513) identified a glutamic acid sup-tRNA that effectively restores CFTR protein expression in CFTR Glu PTC mutants. This project is currently supported by the Cystic Fibrosis Foundation (HUANG25G0) and a biomedical research grant from CTSI.
Furthermore, we have established a CF theragnostic program at IU. CFTR modulators, small molecules that improve CFTR trafficking or increase CFTR channel opening, have been FDA-approved to treat patients with CF who have common CFTR mutations, significantly enhancing their quality of life. However, individuals with rare CFTR mutations do not qualify for this treatment. The theragnostic program involves applying CFTR modulators to nasal cells from patients to determine if CFTR function in these cells can be restored. The goal of this program is to improve access to CFTR modulator treatment for individuals with rare CFTR mutations. Our recent case report study demonstrated that CFTR modulators effectively treated a patient with a ΔI1023_V1024-CFTR mutation (PMID: 40508114).
