Ronald C. Rubenstein, MD, PhD

faculty photo
Associate Professor of Pediatrics
Department: Pediatrics
Graduate Group Affiliations

Contact information
Pulmonary Medicine and Cystic Fibrosis Center
Abramson Center Room 410A
Philadelphia, PA 19104
Office: 215 590-1281
Fax: 215 590-1283
S.B. (Chemistry)
Massachusetts Institute of Technology, 1984.
Ph.D. (Pharmacology)
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.
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Description of Research Expertise

Research Interests
Pharmacologic repair of mutant CFTR function in Cystic Fibrosis.

Key words: Cystic Fibrosis, CFTR, Molecular Chaperone, ENaC, Phenylbutyrate, Protein Trafficking.

Description of Research
We are interested in novel drug therapies for cystic fibrosis (CF). By understanding the molecular defects in the mutant Cystic Fibrosis Conductance Regulatory Protein (CFTR), which is absent in the disease, we aim to use novel pharmaceuticals to overcome these molecular defects and "repair" the dysfunctional CFTR. We hypothesize that, eventually, such "protein repair" agents will improve the health of patients with CF.

We have focused on the repair of the most common CFTR mutation, deltaF508-CFTR, which retaines chloride transport function but is targeted for rapid intracellular degradation and not found at its appropriate location at the apical membrane of epithelia. We are studying one particular "protein repair" agent, sodium 4-phenylbutyrate (4PBA), which allows deltaF508-CFTR to reach the appropriate location in epithelial cells. We are using standard cell and molecular biology in vitro techniques in cultured cells and the Xenopus oocyte model expression system to assess the influence of 4PBA on proteins important in the intracellular trafficking of deltaF508-CFTR. As we identify 4PBA-regulated proteins that interact with deltaF508-CFTR, we aim to perform specific modulations of protein expression that will afford insight into the mechanism and repair of deltaF508-CFTR's aberrant intracellular trafficking. With the recognition that CFTR also regulates the activity of other epithelial ion transporter such as the Epithelial Sodium Channel, ENaC, we are beginning to assess whether repaired mutant CFTR (from a chloride transport perspective) will also interact with and regulate ENaC appropriately. We ultimately aim to extend and translate these observations into clinical trials of 4PBA and other "protein repair" agents in patients with CF.

Rotation Projects for 2006-2007
- Cellular adaptation and modulation of mRNA stability in response to the CFTR-repair agent phenylbutyrate.
- Regulation of intracellular trafficking of CFTR, mutant CFTR, and ENaC by molecular chaperones.
- Trafficking interactions of CFTR and ENaC in epithelial cells.

Lab personnel:
Laurence Suaud, PhD, Research Scientist, Children's Hospital of Philadelphia
Wusheng Yan, MD, Senior Research Technician
Katelyn Miller, High School Intern
Amal Robay, PhD, Post-doctoral Fellow
Larry Copelovitch, MD, Fellow, Pediatric Nephrology
Susan Jarman, Research Technician/Lab Manager

Selected Publications

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 Page: in press, June 2015.

Sheikh, S, Putt, M, Forde, KA, Rubenstein, RC and Kelly A: Elevation of 1-Hour Plasma Glucose During Oral Glucose Tolerance Testing And Pulmonary Function in Cystic Fibrosis. Pediatr Pulmonol Page: in press, May 2015.

Conrad C, Lymp J, Thompson V, Dunn C, Davies Z, Chatfield B, Nichols D, Clancy J, Vender R, Egan M E, Quittell L, Michelson P, Antony V, Spahr J, Rubenstein R C, Moss R B, Herzenberg L A, Goss C H, Tirouvanziam R: Long-term treatment with oral N-acetylcysteine: Affects lung function but not sputum inflammation in cystic fibrosis subjects. A phase II randomized placebo-controlled trial. Journal of cystic fibrosis : official journal of the European Cystic Fibrosis Society 14(2): 219-227, Mar 2015.

Adams Kelly M, Abraham Valsamma, Spielman Daniel, Kolls Jay K, Rubenstein Ronald C, Conner Gregory E, Cohen Noam A, Kreindler James L: IL-17A Induces Pendrin Expression and Chloride-Bicarbonate Exchange in Human Bronchial Epithelial Cells. PloS one 9(8): e103263, 2014.

Grumbach Yael, Bikard Yann, Suaud Laurence, Chanoux Rebecca A, Rubenstein Ronald C: ERp29 Regulates Epithelial Sodium Channel Functional Expression by Promoting Channel Cleavage. American journal of physiology. Cell physiology 307(8): C701-9, 2014.

Sheikh Saba, Zemel Babette S, Stallings Virginia A, Rubenstein Ronald C, Kelly Andrea: Body composition and pulmonary function in cystic fibrosis. Frontiers in pediatrics 2: 33, 2014.

Chanoux RA, Shubin CB, Robay A, Suaud L, Rubenstein RC.: Hsc70 negatively regulates epithelial sodium channel trafficking at multiple sites in epithelial cells. Am J Physiol Cell Physiol. 305: C776–C787, Oct 2013.

Clancy, J.P., Dupont, L., Konstan, M.W., Billings, J., Fustik, S., Goss, C.H., Lymp, J., Minic, P., Quittner, A.L,, Rubenstein, R.C., Young, K.R., Saiman, L., Burns, J.L., Govan, J.R., Ramsey, B. and Gupta, R, for the Arikace Study Group. : Phase II studies of nebulised Arikace in CF patients with Pseudomonas aeruginosa infection. Thorax Jun 2013.

Arkin Lisa M, Flory James H, Shin Daniel B, Gelfand Joel M, Treat James R, Allen Julian, Rubenstein Ronald C, Yan Albert C: High Prevalence of Aquagenic Wrinkling of the Palms in Patients with Cystic Fibrosis and Association with Measurable Increases in Transepidermal Water Loss. Pediatric dermatology 29: 560-6, Sep 2012.

Mueller Gunhild M, Yan Wusheng, Copelovitch Lawrence, Jarman Susan, Wang Zhijian, Kinlough Carol L, Tolino Michael A, Hughey Rebecca P, Kleyman Thomas R, Rubenstein Ronald C: Multiple residues in the distal C terminus of the α-subunit have roles in modulating human epithelial sodium channel activity. American journal of physiology. Renal physiology 303(2): F220-8, Jul 2012.

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Last updated: 06/10/2015
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