beth israel deaconess medical center a harvard medical school teaching hospital

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Seth Alper, MD, PhD

The Alper lab, started by Seth Alper, studies regulation of cellular pH and volume in several diseases associated with malfunctions or mutations in particular ion transporters or ion channels. These include:

Distal renal tubular acidosis, spherocytic and stomatocytic anemias

The Alper lab studies the Cl/HCO3 exchanger SLC4A1/AE1, mutations in which cause these diseases of Type A intercalated cell and erythrocytes.

They also study SlC4A2/AE2, important in function of the acid-secreting gastric parietal cell, osteoclast, and odontoblast, and in basolateral Cl loading of Cl-secretory epithelial cells throughout the body (deficiency in mouse causes osteopetrosis); Slc4A3/AE3, important for pH and chloride regulation in the eye, myocardium, hippocampus, and respiratory control neurons; SLC4A11, important in corneal endothelium; roles of carbonic anhdyrases in regulation of anion exchanger function.

Sickle cell anemia volume regulation

(therapeutic slowing of polymerization of deoxyhemoglobin S by lowering its concentration). The Alper Laboratory studies the following dominant regulators of red cell volume: the IK1/KCNN4 K channel; red cell Cl channel(s); K-Cl cotransporters KCC3, KCC4, and KCC1; and the deoxygenation-activated cation channel, Psickle.

Nephrolithiasis

They study oxalate transporters of the gut and kidney, in particular the SLC26A6 oxalate/Cl exchanger, whose deficiency in the mouse

causes kidney stones. They are characterizing other oxalate transporters as well.

They also study the SCL26A4/pendrin Cl/HCO3 exchanger of the cochlear epithelium and Cl/I exchanger of the thyrocyte, whose deficiency causes Pendred Syndrome; the SLC26A3/DRA Cl/HCO3 exchanger of the enterocye, whose deficiency causes congenital chloridorrhea; the SLC26A2/DTDST sulfate exchanger of the chondrocyte, whose deficiency causes chondrodysplasia. They are determining the structure and function of a mycobacterial SLC26 homolog.

Polycystic kidney disease

The Alper Lab studies the roles of polycystins-1 and 2 in normal flow sensing by ciliated epithelial cells, and the defective flow-sensing of PKD cyst epithelial cells. We also study the role of ATP release and purinergic signaling in that flow sensing. A longer-term goal is to determine if defective flow-sensing is a cause or consequence of the pathogenic polycystin mutations

A former project to which we are returning is exploration of pharmacological blockade of KCNN4 to retard PKD cyst growth.

Other recent projects:

  • Roles of KCNN4 and TRP channels in control and treatment of infectious and inflammatory diarrheas.
  • Role of RhoA in hypertonicity-triggered reorientation of actin cytoskeleton in endothelial cells.
  • Shear stress-induced signaling in endothelial cells.
  • Carbonic anhydrase IX function in renal cell carcinoma.