Biological and Biomedical Science
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Seth L. Alper

Department of Medicine
Molecular and Vascular Medicine Unit and Renal Division
Beth Israel Deaconess Medical Center E/RW 763

330 Brookline Avenue
Boston. MA 02215
Tel: (617) 667-2930
Fax: (617) 667-8040
Email: salper@bidmc.harvard.edu

6 postdoctoral fellows

Seth Alper

We investigate molecular mechanisms of cellular pH and volume regulation in homeostasis and disease, using techniques of molecular cell biology, ion transport and electrophysiology, biochemistry and genetics applied at the molecular, cellular, and organismic levels in multiple model systems. Ongoing projects include the following:

1. Molecular and cellular physiology and genetics of anion exchangers of the SLC4 and SLC26 gene families. SLC4-related human diseases include spherocytic anemia, hydrops fetalis, distal renal tubular acidosis (which we co-discovered), and visual impairment. Individual SLC4 gene disruptions in the mouse can also produce achlorhydria/gastric atrophy, diarrhea, osteopetrosis, and susceptibility to seizures. SLC26-related diseases include life-threatening diarrhea, kidney stone disease, deafness, and goiter. We study structure-function relationships, mechanism, regulation of these transporters in Xenopus oocytes, mammalian cells, and intact tissues. We also work collaboratively with mouse, fish, and worm disease models resulting from loss-of-function of these transporters.


2. The pathophysiology of erythrocyte volume regulation as related to developmental therapeutics of sickle disease and thalassemia. We discovered inhibitors of the Kcnn4 red cell potassium channel, a finding that led to a stage III clinical trial for treatment of sickle disease. These studies have also involved erythroid K-Cl cotransporters and a deoxygenation-activated cation channel as parallel therapeutic targets. We have performed structure-function studies and worked with mouse knockout models to investigate these erythroid volume-regulatory transporter systems, and associated disorders in other organ systems.


3. The intracellular ionic correlates of cell mechanotransduction. These studies currently focus on the signal transduction of fluid flow-sensing by renal epithelial cells and its disruption in polycystic kidney disease. We have also studied flow-sensing and mechanosensitivity in endothelial cells, and pharmacological aspects of intracellular Ca2+ and ionic signaling in other cell types during stimulated secretion or motility. These latter studies have led to investigation of a novel actin cytoskeletal rearrangement in endothelial cells exposed to the hyperosmolar stress experienced during clinical use of intravenous mannitol for acute treatment of intracranial swelling.

 

References:

  • Chernova MN, Jiang L, Friedman DJ, Darman RB, Lohi H, Kere J, Vandorpe DH, Alper SL.  Functional comparison of mouse slc26a6 anion exchanger with human SLC26A6 polypeptide variants: differences in anion selectivity, regulation, and electrogenicity.   J Biol Chem 2005; 280:8564-80.
  • Kurschat CE, Shmukler BE, Jiang L, Wilhelm S, Kim E, Chernova MN, Kinne RH, Stewart AK, Alper SL.  Alkaline-shifted pHo-sensitivity of AE2c1-mediated anion exchange  reveals novel regulatory determinants in the AE2 N-terminal cytoplasmic domain.  J Biol Chem 2006; 281:1885-1896.
  • Xu C, Rossetti S, Jiang L, Harris PC, Brown-Glaberman U, Wandinger-Ness A, Bacallao R, Alper SL.  Human ADPKD primary cyst epithelial cells with a novel, single codon deletion in the PKD1 gene exhibit defective ciliary polycystin localization and loss of flow-induced Ca2+ signaling.  Am J Physiol Renal Physiol 2007; 292:F930-45.
  • Rust MB, Alper SL, Rudhard Y, Shmukler BE, Vicente R, Brugnara C, Trudel M, Jentsch TJ, Huebner CA.  Disruption of erythroid K-Cl cotransporters alters erythrocyte volume and partially rescues erythrocyte dehydration in SAD mice. J Clin Invest 2007; 117:1708-17.
  • Clark JS, Vandorpe DH, Chernova MN, Heneghan JF, Stewart AK, Alper SL. Species differences in Cl- affinity and in electrogenicity of SLC26A6-mediated oxalate/Cl- exchange correlate with the distinct human and mouse susceptibilities to nephrolithiasis. J Physiol 2008; 586:1291-306