Dalton Cardiovascular Research Center

University of Missouri

Silvia G. Bompadre, PhD

Research Interests

Molecular physiology and pharmacology of CFTR channels

Research Description

The Cystic Fibrosis Transmembrane conductance Regulator (CFTR) is a chloride channel that is regulated by phosphorylation and gated by ATP binding and hydrolysis. Mutations in the gene coding for CFTR result in the genetic disease cystic fibrosis (CF), the most common lethal autosomal recessive disorder in white populations. CF is manifested by a defective chloride transport across the epithelial cells in various tissues such as respiratory, gastrointestinal, hepatobiliary, and reproductive tracts.

Dr. Bompadre research focuses on understanding how CFTR works at the molecular level and how mutations in CFTR cause defective functions. The final goal is to apply the acquired knowledge in therapeutic design for CF. The studies are done in collaboration with Dr. Tzyh-Chang Hwang. There are different mechanisms that cause CFTR channels dysfunction. Since some of the defective proteins are present in the apical membrane, pharmacological agents that increase the activity of these mutant channels are of important value in the treatment of cystic fibrosis. Many compounds have been found that increase the CFTR activity. Some agents modulate the activity of the protein kinases and phosphatases that regulate CFTR, whereas others interact directly with CFTR to control the channel activity. However, a detailed understanding, at a molecular level, of how these compounds increase CFTR activity is still lacking. The known potentiators are not potent enough to restore the activity of the CFTR mutants responsible for the most severe phenotypes. Without a detailed understanding of how these compounds work or where they bind, it is very difficult to design a drug that may accomplish the task of rescuing the defective channel. Combining electrophysiology with molecular biology methods and molecular modeling, structure/function studies are set to study CFTR's structure which in turn can help us find specific activators for specific disease-associated mutants. Recently, Dr. Bompadre's studies focused on the mechanisms responsible for the dysfunction of the disease-associated mutant G551D. The importance of understanding its defective gating lies in the facts that this is the third most common mutation associated with CF. We found that unlike normal CFTR, this mutant channel fails to respond to ATP likely because the mutation is located at a critical position for ATP to open the channel. Interestingly, however, the activity of this mutant channel can be greatly increased by using chemically modified ATP analogs. Our findings have opened the door for a knowledge-based drug design to amend the dysfunction of this mutant CFTR.

Professional Background

Selected Publications