Brian P Wellensiek, Ph.D.

Understanding non-traditional protein translation. In contrast to classical eukaryotic translation, which involves the recognition of a cap structure at the 5' end of an RNA message, a growing body of evidence has provided support for the existence of translation that occurs in the absence of a 5' cap. This non-classical mode of protein translation has been shown to play an important role in many cellular events, however little is known regarding the mechanism behind how this is accomplished. In previous research I have identified a large number of sequences, termed translation enhancing elements (TEEs), that can facilitate cap-independent translation. My research now analyzes these sequences and explores their function. More specifically, a 13-nucleotide motif has been identified that has the capacity to modulate cap-independent translation. Further characterization of this motif will allow us to better understand this non-traditional method of protein production.

Using translation enhancing elements to improve human health. The use of the vaccinia virus (VACV) as a vaccine vector was instrumental in the eradication of smallpox in the 1970's. Since this success, research on VACV has produced a number of vaccines, with several strains in development against a wide array of infectious diseases. These viruses range from highly attenuated strains (many of which are replication incompetent) to non-attenuated strains that are fully replication competent. Although many of the non-attenuated strains are highly immunogenic, they are often poor vaccine candidates due to higher than normal complication rates associated with the replication of VACV within the patient. Conversely, non-replicating viral vectors provide increased safety but are often not immunogenic enough to make potent vaccines. My research aims to address this problem by introducing previously identified TEEs into attenuated VACV vaccine strains to increase antigen production and therefore increase the efficiency of these vaccines. Furthermore, my research aims to improve the efficacy of mRNA-based vaccines. A critical barrier in improving mRNA vaccine efficacy is increasing protein antigen production without a corresponding increase in systemic reactions triggered by the mRNA vaccine components. Through the incorporation of TEEs to increase expression of the antigen of interest, the goal of my research is to improve immune system responses to the antigen while lowering the dosage needed for administration to patients.