ABOUT THE GRANT

Cystic fibrosis is caused by dysfunctional mutations in CFTR, a critical chloride channel expressed in the airway.
In the absence of CFTR activity, mucus is thick and sticky, mucocilliary clearance is impaired, and the innate antimicrobial
activities of mucus are defective. Recently, highly effective modulator therapies (HEMTs) that partially correct CFTR
function have been introduced. While these therapies have had a marked impact, there is motivation to identify new
strategies to rescue mucus function because: 1) about 8% of CF patients have class I dysfunctional mutations,
which are not treatable with HEMTs; 2) for other patients where HEMTs are appropriate, variable efficacy is observed;
and 3) the long-term effectiveness of HEMTs is unknown. An alternative strategy is to target another chloride
channel in the airway that could compensate for reduced CFTR activity. Such an approach should be appropriate
for all CF patients. In this regard, we have shown that the calcium-activated chloride channel TMEM16A can serve this
function. We have identified and engineered a protein that can specifically potentiate TMEM16A called CLCA1 VWA, and
we have shown that this approach rescues mucus function in CF airway models. We have also found that a unique form
of TMEM16A, which may have increased activity, is expressed in CF airways. The purpose of this project is to investigate
the activation properties of this form of TMEM16A, and characterize the cells and pathways that mediate its function.
The results could lead to new therapeutic approaches to treat CF or improve current HEMT regimens as add-on therapy,
and should be effective for the subset of CF patients for which there are no current effective corrector therapies.

Dr. Brett obtained his B.S. in Chemistry from North Dakota State University and completed his PhD studies in Chemistry at the University of Nebraska-Lincoln. He then proceeded to a Postdoctoral Fellowship in the lab of Professor Daved Fremont at Washington University School of Medicine (Department of Pathology and Immunology), where he focused on structural, biophysical and mechanistic studies of clathrin-mediated endocytosis, immune signaling, and host-virus interactions. Following his postdoctoral work, he was recruited to the Department of Medicine (Pulmonary Division) at Washington University School of Medicine where he establish a structural biology lab with a focus on molecular mechanisms of disease and drug discovery. He currently serves as the Co-Director of the Biochemistry, Biophysics, and Structural Biology PhD program at Washington University.

One focus of Dr. Brett’s group has been the regulation of ion channels in the airway, which is critical in Cystic Fibrosis (CF) and other inflammatory airway diseases. His lab discovered a protein, CLCA1, that can selectively activate a chloride channel (TMEM16A) in the airway. In collaboration with Jen Alexander- Brett’s lab, they were able to show that CLCA1 could activate TMEM16A in CF airway tissues and rescue mucus functions, indicating that this could be an alternative therapeutic route to treat CF. The current project supported by the RFRF seeks to elucidate mechanistic details to enable future development of such alternative CF treatments.