Replication deficient recombinant adenoviruses (rAv) are potent vectors for DNA transfer (transduction). Diabetic glomerulosclerosis is a potential target for rAv-based forms of gene therapy. The coxsackie adenovirus receptor protein (CAR) mediates rAv infection. Despite widespread use of rAv, the mechanisms of CAR-mediated viral entry into cells are not well characterized. Therefore, the scientific objective of this proposal is to define CAR receptor expression, function, and utility in controlling transduction. The project has 3 Specific Aims.
Aim #1 will further characterize the expression of CAR in normal and diabetic kidney.
Aim #2 will investigate the functional consequences of rAv engagement of CAR under normal and diabetic conditions. Beginning with DNA microarray analysis followed by confirmatory studies using quantitative PCR, the gene activation profile resulting from CAR engagement by rAv will be elucidated.
Aim #3 will explore the clinical utility of CAR in regulating rAv mediated gene transfer. The goal of this aim is to control rAv transduction by using a doxycycline-responsive CAR transgene. Taken together, these studies will define CAR expression, function, and utility in the development of rAv-based forms of gene therapy for diabetic glomerulosclerosis. The scientific goals of this project are a natural extension of the candidate's current studies (NIH 1F32 DK10064-01). The educational curriculum developed by the candidate and his sponsors will complement the scientific studies in developing a comprehensive training experience. The educational curriculum employs a multi-faceted approach consisting of didactics, seminars, and meetings. These activities provide the foundation for the applicant in the pursuit of a career as a physician scientist. The long-term career goal is to develop into a translational scientist with all of the clinical and basic investigative tools necessary to design and apply novel forms of gene therapy for kidney disease. In this regard, the candidate will continue his relationship with his current mentor, N. S. Nahman, Jr., M.D. Dr. Nahman provides an excellent role model as a clinician scientist. Chandan K. Sen, Ph.D., serves as a cosponsor on the project and brings a diverse background in the basic sciences for the candidate's training plan. Thus, the candidate's scientific plan, educational curriculum, and association with effective mentors ensure an excellent career development experience.
