Ron Rubenstein, MD, PhD
Associate Professor, Dept of Pediatrics

Gene Therapy and Vaccines Program

Address

Children's Hospital of Philadelphia
410C Abramson Research Center
Philadelphia, PA 19104-4399

Office tel.: 215 590-1281
Lab tel.: 215 590-3819
Fax: 215 590-1283
E-mail: rrubenst@mail.med.upenn.edu
or rubensteinr@email.chop.edu


Education

Massachusetts Institute of Technology: S.B. (Chemistry), 1984.

University of Texas Southwestern Medical Center: Ph.D. (Pharmacology), 1990.

University of Texas Southwestern Medical Center: M.D. (Medicine), 1991.

Research Interests

• Pharmacologic repair of mutant CFTR function in Cystic Fibrosis.

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

Search PubMed for articles

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.

Recent Publications

Yan, W., Samaha, F.F., Ramkumar, M., Kleyman, T.R., and Rubenstein, R.C. (2004) CFTR Differentially Regulates Human and Murine Epithelial Sodium Channels in Xenopus Oocytes. J. Biol. Chem., 279:23183-23192.

Samaha, F.F.,* Rubenstein, R.C.,*# Yan, W.,* Ramkumar, M., Levy, D.I., Ahn, Y.J., Sheng, S. and Kleyman, T.R. (2004) Functional Polymorphism in the Carboxyl Terminus of the Alpha Subunit of the Epithelial Sodium Channel Alters Surface Expression in Xenopus Oocytes. J. Biol. Chem., 279:23900-23907.
*Equal Contribution, #Corresponding Author

Yan, W., Suaud, L., Kleyman, T.R., and Rubenstein, R.C. (2006) Differential Modulation of a Polymorphism in the Carboxyl Terminus of the Alpha Subunit of the Human Epithelial Sodium Channel by Protein Kinase C d. Am. J. Physiol.-Renal Physiol. 290:F279-F288.

Goldfarb, S.B., Kashlan, O.B., Watkins, J.N., Suaud, L., Yan, W., Kleyman, T.R. and Rubenstein, R.C. (2006) Differential Effects of Hsc70 and Hsp70 on the Intracellular Trafficking and Functional Expression of Epithelial Sodium Channels. Proc. Nat. Acad. Sci. U.S.A., 103:5817-22.

Suaud, L., Yan W. and Rubenstein, R.C. (2007) Abnormal Regulatory Interactions of I148T-CFTR and the Epithelial Na+ Channel in Xenopus Oocytes. Am. J. Physiol Cell Physiol, 292:C603-11.

Lab

Rotation Projects

• 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
Elizabeth Fiorino, MD, Fellow, Pediatric Pulmonology
Katelyn Miller, High School Intern
Ellen Lide, Research Technician
Michele Scheerer, Research Technician/Lab Manager