Elevated erythrocyte adenosine deaminase (ADA) activity has been reported in association with hereditary hemolytic anemia (Valentine et al., Science 195:783-5, 1977). Preliminary studies have shown that this disorder is due to overproduction of ADA in proband red blood cells and that the defect results in increased translational efficiency of reticulocyte ADA mRNA. We propose to define this disorder further by: 1) verifying that the defect is intrinsic to ADA mRNA, 2) defining the mutation at a molecular genetic level, 3) investigating the factors which regulate the translational activity of ADA mRNA in mutant and normal cells, and 4) exploring the mechanism of tissue-specific control of ADA activity. This project may provide valuable insights into the regulation of ADA activity and into control of translational events and tissue-specific expression of proteins in general. Characterization of the mutation in ADA overproduction may also provide information which could aid in the development of ADA expression vectors for gene transfer therapy in severe combined immunodeficiency syndrome. The preliminary studies have been conducted by the principal investigator during two years of research fellowship under the direction of Dr. Beverly Mitchell. Dr. Chottiner currently holds a tenure-track position in the Division of Hematology and Oncology. This project has provided the foundation for a career in research by exposing the investigator to approaches to problem solving in the laboratory and to concepts and techniques in metabolism, immunology, and molecular genetics. Ongoing advice and active support for the investigator and this project are available from Drs. Mitchell and Ginsburg as well as several on-site investigators with experience in molecular genetics, cell biology, hematopoiesis, and protein chemistry.
| Chottiner, E G; Shewach, D S; Datta, N S et al. (1991) Cloning and expression of human deoxycytidine kinase cDNA. Proc Natl Acad Sci U S A 88:1531-5 |
