Cystic Fibrosis; Kidney; Nephrology; Sharks; Chloride Channels; Cystic Fibrosis Transmembrane Conductance Regulator; SNARE Proteins
In the common genetic disease, cystic fibrosis, mutations in a transmembrane chloride channel the cystic fibrosis transmembrane regulator (or CFTR) are responsible for clinical manifestations in many organs (lung, pancreas, GI tract). The most common mutation (delta F 508) results in defective trafficking of the protein to the cell membrane. Agents that reverse this abnormality or that increase the driving force for chloride secretion have the potential to treat this disease.
Specialized Terms: Cystic fibrosis; CFTR; Kidney; Chloride channels; Shark rectal gland
Extensive Research Description
In the common genetic disease, cystic fibrosis, mutations in a transmembrane chloride channel the cystic fibrosis transmembrane regulator or CFTR) are responsible for clinical manifestations in many organs (lung, pancreas, GI tract). The most common mutation (delta F 508) results in defective trafficking of the protein to the cell membrane. Agents that reverse this abnormality or that increase the driving force for chloride secretion have the potential to treat this disease.
We are studying the structure, function and regulation of CFTR and other chloride channels in several sodium chloride secreting epithelia, including mammalian airway cells, the kidney and the shark salt gland. Specific projects include:
- Regulation of CFTR trafficking from ER to cell membrane
- Defining the role of SNARE proteins and VAMP in the trafficking defect and possible reversal of the CF phenotype
- Identification of the role of CFTR in the human renal disease, adult polycystic kidney disease
- K2P Role of K2P potassium channels in chloride secreting epithelia.
We are also carrying out physiological, molecular and structural studies of novel G protein coupled receptors and natriuretic peptide receptors involved in the regulation of chloride transport in marine models. This work is done both at Yale and at the Mount Desert Island Biological Laboratory in Bar Harbor, Maine. Students will learn molecular techniques of cloning, sequencing, expression, site specific mutagenesis and will couple these techniques to structural (confocal microscopy using GFP constructs, protein purification and crystallography) and electrophysical measurements.Dr. Forrest is also carrying out clinical studies in fluid and electrolyte disorders, including lithium inducted diabetes insipidus, lithium intoxication, and hyponatremia.
- Telles CJ, Decker SE, Motley WW, Peters AW, Mehr AP, Frizzell RA, Forrest JN, Jr., Am J Physiol Cell Physiol 311: C000–C000, 2016. First published September 21, 2016; doi:10.1152/ajpcell.00030.2016
- Forrest J.N. Jr., J Am Soc Nephrol. (2009 Aug); Franklin H. Epstein: reminiscences of a brilliant physician-scientist and master clinician. 20(8):1651-3. Epub 2009 Jul 16
- Bewley MS, Pena JT, Plesch FN, Decker SE, Weber GJ, Forrest JN.. Jr. (2006) Shark rectal gland vasoactive intestinal peptide receptor: cloning, functional expression, and regulation of CFTR chloride channels. Am J Physiol Regul Integr Comp Physiol. 2006 Oct;291(4):R1157-64. Epub 2006 May 25.
- Mattingly CJ, Rosenstein MC, Colby GT, Forrest JN Jr, Boyer JL. (2006) The Comparative Toxicogenomics Database (CTD): a resource for comparative toxicological studies. J Exp Zoolog A Comp Exp Biol. 2006 Sep 1;305(9):689-92.
- Weber GJ, Mehr AP, Sirota JC, Aller SG, Decker SE, Dawson DC, Forrest JN Jr. (2006) Mercury and zinc differentially inhibit shark and human CFTR orthologues: involvement of shark cysteine 102. Am J Physiol Cell Physiol. 2006 Mar;290(3):C793-801. Epub 2005 Oct 19.
- Valentich, J.D. and Forrest, J.N., Jr. (1991) Cl–secretion by cultured shark rectal gland cells. I. Transepithelial transport. Am. J. Physiol. 260:C813–C823
- Kelley, G.G., Poeschla, E.M., Barron, H.V., and Forrest, J.N., Jr. (1990) A1 adenosine receptors inhibit chloride transport in the shark rectal gland. Dissociation of inhibition and cyclic AMP. J. Clin. Invest. 85:1629–1636