Cell Biology Annual Report 2010-11 (FY 2011) - Department of Cell ...

CBP Faculty Research Summaries
Cell Biology and Physiology
Annual Report
Raymond A. Frizzell, Ph.D.
Professor
Director of Cystic Fibrosis Research Center
Dr. Frizzell’s interests concern the mechanisms of salt and water transport in secretory and
absorptive epithelia and pathways that regulate these processes. Specifically, we are defining
defects in ion transport regulation in the genetic disease, cystic fibrosis (CF), membrane
trafficking of wild-type and mutant ion channel proteins, gene expression and therapeutic
strategies. Since most CF is caused by the cellular destruction of misfolded mutant CF
proteins, our main research efforts focus on defining the steps in the biogenesis of the CF protein
(CFTR), and the quality control checkpoints where mutant CFTR proteins go ‘off-pathway’ and
are degraded by the proteasome. CFTR processing can be viewed as a ‘bucket brigade’ in which
protein is passed from checkpoint to checkpoint and some is lost at each step. Therefore, it is
important to know quantitatively the contribution of each step to the loss of CFTR protein so
that the major one(s) can be targeted for drug development. Recently, we have described novel
interactions of CFTR with chaperones called small heat shock proteins, which we have found to
catalyze the addition of SUMO, a ubiquitin related modifier, to selectively target mutant CFTR
for degradation. The selectivity of this pathway for mutant CFTR appears to extend also to
misfolded proteins that lead also to neurodegenerative diseases, and the results implicate the
components of this pathway as therapeutic targets for correcting mutant protein biogenesis.
Finally, we have identified an alternative anion channel at the apical membranes of airway
epithelial cells, and we are examining its contribution to salt and water secretion in the
formation of airway surface liquid. This channel interacts tightly with CFTR, regulates its
activity, and their interaction influences the biogenesis of both proteins. The activation of this
channel could provide an alternative to CFTR for regulation of airway liquid properties.
We also study the regulation of epithelial sodium transport in airway epithelia and the distal
nephron of the kidney. Our interests lie in identifying the factors that control the apical
membrane density of the sodium entry channel, ENaC, and how the mechanisms of apical
insertion, retrieval and recycling influence sodium absorption. The role of 14-3-3 protein
binding is a current interest in the regulation of both CFTR and ENaC trafficking, and 14-3-3
affinity capture methods are being used to identify new traffic proteins that are phosphorylated
by regulators such as aldosterone and vasopressin. Defects in these processes influence the
severity of both cystic fibrosis and hypertension.
Vernon L. Gay, Ph.D.
Associate Professor
Dr. Gay began his training in reproductive endocrinology as a graduate student at Indiana
University in Bloomington. While there he devised a technique for rapid transauricular
hypophysectomy of rats and used available bioassays to obtain the first measurements of the half
lives of endogenous LH and FSH in the rat.
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For his post-doctoral work Dr. Gay moved to the University of Michigan in Ann Arbor at a time
when radio-immunoassays for gonadotropins (LH and FSH) were first available. In addition
to describing hormone profiles throughout the reproductive cycle of the female rat, he was one
of the first to describe the phenomenon of pulsatile pituitary hormone secretion in any species
(specifically the castrated rat).