Ronald C. Rubenstein, MD, PhD
Abramson Center Room 410A
34th & CIVIC CENTER BLVD
Philadelphia, PA 19104
Fax: 215 590-1283
Massachusetts Institute of Technology, 1984.
Medical Scientist Training Program, The University of Texas Southwestern Medical Center at Dallas, Southwestern Medical School, 1990.
Medical Scientist Training Program, The University of Texas Southwestern Medical Center at Dallas, Southwestern Medical School, 1991.
Description of Research ExpertiseResearch Interests
Pharmacologic repair of mutant CFTR function in Cystic Fibrosis.
Key words: Cystic Fibrosis, CFTR, Molecular Chaperone, ENaC, Phenylbutyrate, Protein Trafficking.
Description of Research
I initially developed my interest in the molecular basis of drug action and my goal to design new drug threapies as an undergraduate at MIT, and began to hone this interest as a student in the Medical Scientist Training Program at UT-Southwestern. Building on the the biochemical techniques learned during my graduate training in molecular pharmacology and my clinical interest in Cystic Fibrosis, my primary research focus has been on basic (laboratory) and translational (clinical) studies of novel means to correct the dysfunction of mutant CFTR proteins. My initial in vitro work as a fellow demonstrated that sodium 4-phenylbutyrate (4PBA) improved the intracellular trafficking and function of the most common CFTR mutation in CF, ΔF508. These data led to our pilot clinical trial of 4PBA that demonstrated small improvments in ΔF508 function in people with CF. These data were a crucial proof of concept that havesupported larger efforts to identify correctors of ΔF508 traffikcing and function.
Our investigations into the mechanism(s) underlying this effect have focused on how 4PBA regulated molecular chaperones modulate the trafficking of CFTR in epithelial cells and other model systems. Because relative hyperfunction of the epithelial sodium channel (ENaC) is a characteristic feature of the CF airway, we have incresingly focused on how these 4PBA-regulated chaperones influence ENaC trafficking, as well as how CFTR itself may modulate ENaC traffikcing and function. Through these studies, my 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.
We have recently developed a keen mechanistic (laboratory) and translational (clinical) interest in Cystic Fibrosis Related Diabetes Mellitus (CFRD), which is an emerging clinical problem that increases morbidity and mortality in people with CF. The underlying basis of CFRD remains poorly understood, and we are beginning to apply things learned from our previous work to these problems as well.
Selected PublicationsKelly, A., DeLeon, D.D., Sheikh, S., Camburn, D., Kubrak, C., Peleckis, A.J., Stefanovski, D., Hadjiliadis, D., Rickels, M.R. and Rubenstein, R.C.: Islet Hormone and Incretin Secretion in Cystic Fibrosis Following 4-months of Ivacaftor Therapy. Am. J. Resp. Crit. Care Med. 199: 342, 2019.
Bikard, Y.*, Viviano, J.*, Orr, M.N., Brown, L., Brecker, M., Jeger, J.L., Grits, D., Suaud, L. and Rubenstein, R.C. *Equal contribution: The KDEL receptor has a role in the biogenesis and trafficking of the Epithelial Sodium Channel (ENaC). J. Biol. Chem. 294: 18324-18336, 2019.
Hong, G., Alby, K., Ng, S.C.W., Fleck, V., Kubrak, C., Rubenstein, R.C., Dorgan, D.J., Kawut, S.M. and Hadjiliadis, D.: The Presence of Aspergillus fumigatus is Associated with Worse Respiratory Quality of Life in Cystic Fibrosis. . J. Cystic Fibrosis 2019.
Kilberg, M., Sheikh, S., Stefanovski, D., Kubrak, C., DeLeon, D., Hadjiliadis, D., Rubenstein, R.C., Rickels, M.R. and Kelly, A.: Dysregulated Insulin in Pancreatic Insufficient Cystic Fibrosis with Post-Prandial Hypoglycemia. J. Cystic Fibrosis 2019.
Nyirjesi, S.C., Sheikh, S., Hadjiliadis, D., DeLeon, D.D., Peleckis, A.J., Eiel, J.N., Kubrak, C., Stefanovski, D., Rubenstein, R.C., Rickels, M.R. and Kelly, A. : Beta-cell Secretory Defects are Present in Pancreatic Insufficient Cystic Fibrosis with 1-hour OGTT Glucose ≥155 mg/dL. J. Cystic Fibrosis 19: 1173, 2019.
Nyirjesi, S.C., Sheikh, S., Hadjiliadis, D., DeLeon, D.D., Peleckis, A.J., Eiel, J.N., Kubrak, C., Stefanovski, D., Rubenstein, R.C., Rickels, M.R. and Kelly, A. : Beta-cell Secretory Defects are Present in Pancreatic Insufficient Cystic Fibrosis with 1-hour OGTT Glucose ≥155 mg/dL. Pediatr. Diabetes Page: in press, May 2018.
Kazmerski, T.M., Sawicki, G.S., Miller, E., Jones, K.A., Abebe, K.Z., Tuchman, L.K., Ladores, S., Rubenstein, R.C., Sagel, S.D., Weiner, D.J., Pilewski, J.M., Orenstein, D.M. and Borrero, S.: Sexual and reproductive health behaviors and experiences of young women with cystic fibrosis J. Cystic Fibrosis 17: 57-63, January 2018.
Kazmerski, T.M., Sawicki, G.S., Miller, E., Jones, K.A.,Abebe, K.Z., Tuchman, L.K., Ladores, S., Rubenstein, R.C., Sagel, S.D., Weiner, D.J., Pilewski, J.M., Orenstein, D.O. and Borrero, S.: Sexual and reproductive health care utilization and preferences reported by young women with cystic fibrosis J. Cystic Fibrosis 17: 64-70, January 2018.
Sheikh Saba, Gudipaty Lalitha, De Leon Diva D, Hadjiliadis Denis, Kubrak Christina, Rosenfeld Nora K, Nyirjesy Sarah, Pelekis Amy, Malik Saloni, Stefanovski Darko, Cuchel Marina, Rubenstein Ronald C, Kelly Andrea, Rickels Michael R: Reduced β-Cell Secretory Capacity in Pancreatic Insufficient, But Not Pancreatic Sufficient, Cystic Fibrosis Despite Normal Glucose Tolerance. Diabetes 66: 134-144, January 2017.
Moss, RB, Flume, PA, Elborn, JS, Cooke, J, Rowe, SM, McColley, SA, Rubenstein, RC, Higgins, M on behalf of the VX11-770-110 (KONDUCT) Study Group: Efficacy and safety of ivacaftor in patients with cystic fibrosis who have an Arg117His-CFTR mutation: a double-blind, randomised controlled trial. Lancet Respir Med 3: 524-33, July 2015.