Associate Professor of Pharmacology and Toxicology
Adjunct Associate Professor of Chemistry
Director, Dartmouth College Superfund Basic Research Program
Department of Pharmacology and Toxicology
Dartmouth Medical School
7650 Remsen - Room 514
Hanover NH 03755-3835
phone: 603-650-1316
fax: 603-650-1129
e-mail: josh.hamilton@dartmouth.edu
 
 

The overall goal of our research is to develop new clinical strategies for treatment of cystic fibrosis (CF), based on systemic administration of pharmacological agents that will increase functional cell surface protein expression of the mutant DF508 cystic fibrosis transmembrane conductance regulator (CFTR) protein. Although there are hundreds of individual CFTR mutations, the DF508 CFTR mutation accounts for over 67% of all CF cases. In this mutation, the biochemical defect appears to be one of folding and trafficking, such that functional CFTR does not reach the cell surface. However, experimental techniques in cell culture that can overcome this blockade have demonstrated that if this mutant protein can be trafficked to the cell surface, it functions normally. It has been calculated that only a small fraction of normal expression level is needed to provide a clinically significant impact on the disease phenotype. Thus, strategies that can increase DF508 CFTR expression and/or trafficking to the cell surface would be expected to have clinical benefit to these CF patients, and these strategies may also be applicable to several other CF mutations of the same class. We recently demonstrated that two different cancer chemotherapy drugs, mitomycin C (MMC), a DNA crosslinking agent, and doxorubicin (Dox), an anthracycline, significantly increased expression of CFTR mRNA levels, total cellular and membrane-associated CFTR protein levels, and CFTR-associated chloride currents in human epithelial cells. We have also recently shown that Dox caused a two-fold increase in DF508 CFTR associated chloride currents in a canine MDCK derived cell line that expresses a stably transfected copy of human DF508 CFTR. The overall aim of this project is to determine the underlying mechanism for these effects, so as to provide information useful in developing subsequent screens for drugs that can induce optimal DF508 CFTR expression at the cell surface with minimal toxicity. The specific objective of this proposal is to determine the mechanistic basis for the effects of Dox on CFTR and DF508 CFTR mRNA and protein expression. In particular, we will test the hypothesis that Dox increases CFTR and DF508 CFTR mRNA expression and/or CFTR and DF508 CFTR protein trafficking to the cell surface as the principal means by which it increases their functional surface expression.  Our longer range goal will be to identify drugs which share the ability to increase DF508 CFTR functional expression while minimizing patient toxicity, with the aim of developing clinically useful drugs for treatment of CF patients to ameliorate their disease phenotype.
 

Related Links

My home page also includes a brief bio and description of my overall research interests, and can be found at:
http://www.dartmouth.edu/~cehs/hamilton.shtml

The Center for Environmental Health Sciences program project also has a web page, which includes a more detailed description of my lab's Superfund and metals related research and the overall program, and can be found at:
http://www.dartmouth.edu/~cehs/home.shtml