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
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 and Axolotl oocytes, mammalian cells, and intact tissues. We also work with collaborators on 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: For a complete listing of publications on PubMed, click here.