John Forrest Jr, MD
Research & Publications
Biography
News
Locations
Research Summary
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.
Research Interests
Cystic Fibrosis; Kidney; Nephrology; Sharks; Chloride Channels; Cystic Fibrosis Transmembrane Conductance Regulator; SNARE Proteins
Selected Publications
- Functional and molecular identification of a TASK-1 potassium channel regulating chloride secretion through CFTR channels in the shark rectal gland: implications for cystic fibrosisTelles CJ, Decker SE, Motley WW, Peters AW, Mehr AP, Frizzell RA, Forrest JN. Functional and molecular identification of a TASK-1 potassium channel regulating chloride secretion through CFTR channels in the shark rectal gland: implications for cystic fibrosis American Journal Of Physiology - Cell Physiology 2016, 311: c884-c894. PMID: 27653983, PMCID: PMC5206301, DOI: 10.1152/ajpcell.00030.2016.
- Franklin H. Epstein: Reminiscences of a Brilliant Physician-Scientist and Master ClinicianForrest JN. Franklin H. Epstein: Reminiscences of a Brilliant Physician-Scientist and Master Clinician Journal Of The American Society Of Nephrology 2009, 20: 1651-1653. PMID: 19608700, DOI: 10.1681/asn.2009050549.
- The Comparative Toxicogenomics Database (CTD): a resource for comparative toxicological studiesMattingly CJ, Rosenstein MC, Colby GT, Forrest JN, Boyer JL. The Comparative Toxicogenomics Database (CTD): a resource for comparative toxicological studies Journal Of Experimental Zoology Part A Ecological And Integrative Physiology 2006, 305A: 689-692. PMID: 16902965, PMCID: PMC1586110, DOI: 10.1002/jez.a.307.
- Shark rectal gland vasoactive intestinal peptide receptor: cloning, functional expression, and regulation of CFTR chloride channelsBewley MS, Pena JT, Plesch FN, Decker SE, Weber GJ, Forrest JN. Shark rectal gland vasoactive intestinal peptide receptor: cloning, functional expression, and regulation of CFTR chloride channels AJP Regulatory Integrative And Comparative Physiology 2006, 291: r1157-r1164. PMID: 16728467, DOI: 10.1152/ajpregu.00078.2006.
- Mercury and zinc differentially inhibit shark and human CFTR orthologues: involvement of shark cysteine 102Weber GJ, Mehr AP, Sirota JC, Aller SG, Decker SE, Dawson DC, Forrest JN. Mercury and zinc differentially inhibit shark and human CFTR orthologues: involvement of shark cysteine 102 American Journal Of Physiology - Cell Physiology 2005, 290: c793-c801. PMID: 16236827, DOI: 10.1152/ajpcell.00203.2005.
- Cl- secretion by cultured shark rectal gland cells. I. Transepithelial transportValentich JD, Forrest JN. Cl- secretion by cultured shark rectal gland cells. I. Transepithelial transport American Journal Of Physiology 1991, 260: c813-c823. PMID: 2018113, DOI: 10.1152/ajpcell.1991.260.4.c813.
- A1 adenosine receptors inhibit chloride transport in the shark rectal gland. Dissociation of inhibition and cyclic AMP.Kelley GG, Poeschla EM, Barron HV, Forrest JN. A1 adenosine receptors inhibit chloride transport in the shark rectal gland. Dissociation of inhibition and cyclic AMP. Journal Of Clinical Investigation 1990, 85: 1629-1636. PMID: 1970583, PMCID: PMC296615, DOI: 10.1172/jci114614.