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Dr. Rubenstein's research focuses on basic and translational studies of novel means to improve outcomes in cystic fibrosis. He initially focused on correcting the dysfunction of mutant cystic fibrosis transmembrane conductance regulator (CFTR) proteins, which led him to study how molecular chaperones regulate the biogenesis and trafficking of CFTR and other proteins that are relevant to cystic fibrosis.
Dr. Rubenstein's research centers on the basic and translational mechanisms underlying the pathophysiology of cystic fibrosis, especially novel means to correct the dysfunction of mutant CFTR proteins. His initial in vitro work demonstrated that sodium 4-phenylbutyrate (4PBA) improved the intracellular trafficking and function of the most common CFTR mutation, F508del. This led to a pilot clinical trial of 4PBA that showed improvements in DF508 function in people with CF. These findings were a crucial proof of concept that led to larger efforts to identify correctors of F508del trafficking and function that are now approved drugs.
His investigations have also focused on how 4PBA regulated molecular chaperones modulate the trafficking of CFTR in epithelial cells and model systems. Dr. Rubenstein has increasingly focused on how these 4PBA-regulated chaperones influence epithelial sodium channel (ENaC) trafficking, as well as how CFTR itself may modulate ENaC trafficking and function. He is particularly interested in ERp29, a novel chaperone of the endoplasmic reticulum and the first luminal chaperone to positively regulate CFTR biogenesis. Through these studies, his lab has gained significant expertise in molecular and physiologic techniques, including Ussing chambers, to study epithelial ion channel trafficking and function, as well as in the detection of CFTR and ENaC.
Dr. Rubenstein recently developed an interest in cystic fibrosis-related diabetes mellitus (CFRD), an emerging clinical problem that increases morbidity and mortality in people with CF.
Among his notable career accomplishments, Dr. Rubenstein:
- Performed first translational clinical trial of small molecule therapy aimed at correcting mistrafficking of F508del CFTR.
- Was the first to show the highly homologous 70 kDa heat shock proteins Hsc70 and Hsp70 are not functionally identical.
- Demonstrated that ERp29 promotes the biogenesis of CFTR; ERp29 is the first ER luminal chaperone that was shown to have this function.
Education and Training
SB, Massachusetts Institute of Technology (Chemistry), 1984
PhD, University of Texas Southwestern Medical Center at Dallas (Pharmacology), 1990
MD, University of Texas Southwestern Medical Center at Dallas, 1991
Fellowship, Johns Hopkins School of Medicine (Pediatric Pulmonology), 1997
Titles and Academic Titles
Director, Cystic Fibrosis Center
Richard B. Johnston Jr. Endowed Chair in Pediatrics
Professor of Pediatrics
Institute for Translational Medicine and Therapeutics, University of Pennsylvania, 2007-
Helen B. Taussig Award for Post-doctoral Clinical Research, The Johns Hopkins School of Medicine, 1997
Faculty Teacher of the Year, Pediatrics Housestaff of Children's Hospital of Philadelphia, 2006