The processing of waste nitrogen in the human liver is a vital hepatic function, and inborn errors in this pathway are fatal or seriously debilitating unless recognized and treated early. Carbamyl phosphate synthetase I (CPSI) is a hepatic mitochondrial enzyme encoded by genomic sequence which carries out the initial step of this urea cycle. Like all components of the pathway, CPSI exhibits a high degree of tissue-specific expression. To better understand the pathophysiology of CPSI deficiency (CPSID), I propose to characterize the genetic mutations in a number of affected patients from diverse ethnic backgrounds. Samples currently in my laboratory from 40 patients will be analyzed by gene scanning and sequencing techniques in order to determine the molecular defects in CPSI. In order to explore the effect of these mutations in vitro, I propose developing a CPSI expression vector which will be used to study the structure and function of both normal and mutant protein. I also propose developing a eukaryotic expression vector with the potential for in vivo replacement of this essential hepatic enzyme. The development of these expression systems will provide a model for modulating hepatic enzyme activity, and will provide a mechanism for evaluating drug interactions and pharmacologic treatment regimens as well.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29DK046965-02
Application #
2146283
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1993-08-01
Project End
1998-07-31
Budget Start
1994-08-01
Budget End
1995-07-31
Support Year
2
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Pediatrics
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212