THE ROLE OF THE COLLECTING DUCT IN DEFENSE OF THE LOWER URINARY SYSTEM IN CONGENITAL AND ACQUIRED UROPATHIES
PIs: Jonathan Barasch, M.D., Ph.D.; Andong Qiu, Ph.D.; Neal Paragas, Ph.D.
The project will capitalize on the lab’s identification of the basic biology of the intercalated cell (IC)(Schwartz, Barasch, Al-Awqati, Nature 1985). They recognized that VUR and obstruction of many different etiologies resulted in a syndrome of alkalinized urine, kidney infections and tubulointerstitial damage suggesting defective function of the kidney’s collecting ducts particularly their IC’s. Their lab showed that the cells are members of the innate immune family of cells–they acidify the urine, they are components of an intratubular iron recovery system, and they generate the bacteriostic protein NGAL (JCI, Molecular Cell, Developmental Cell), which interrupts iron transport to urinary bacteria (Nature Chemical Biology) and is intensely expressed in urinary obstruction and kidney damage (Nature Medicine, Annals of Internal Medicine, JACC).
This proposal will capitalize on the new findings that the IC cells are defective in obstructive abnormalities of the urogenital tract. The lab proposes a two-hit model leading to the common finding of urinary infection: they will characterize a role for urinary reflux as well as a role for intercalated cells in the infection and scarring process. Their work will be aided by their recent discovery of a transcription factor that regulates IC development and by a multicenter international collaborative study of kidney disease that Dr. Barasch directed.