Brian Wellensiek, Ph.D.

Assistant Professor


Midwestern University
College of Health Sciences
Biomedical Sciences Program 
Cactus Wren 306-C
19555 N. 59th Ave.
Glendale, AZ  85308

Office: (623) 572-3222
e-mail: bwelle@midwestern.edu

EDUCATION

Ph.D. Microbiology & Immunology University of Arizona 2007
B.S. Biology University of Nebraska-Lincoln 2002

RESEARCH SUMMARY

The classical model for eukaryotic translation initiation involves linear scanning, a cap-dependent process in which the ribosome recognizes a 7-methylguanosine cap at the 5' end of the RNA message and scans the 5' untranslated region (5' UTR) for an appropriate start site. Alternatively, a growing body of evidence suggests that cap-independent (CI) mechanisms play an important role during many cellular events where cap-dependent scanning is inhibited. There are multiple proposed models, such as recognition of secondary structures, or direct base pairing to the ribosome, that describe how RNA leader sequences initiate translation independent of a 5'cap. However, a detailed understanding of the mechanism of CI translation and its potential contribution to the human proteome has been limited by the absence of effective tools needed to identify these sequences in the human genome. With this challenge in mind, we developed an in vitro selection strategy that makes it possible to search entire genomes for RNA sequences that enhance CI translation initiation. This method entails mRNA display of a library with trillions of genomic fragments, selection for translation initiation, and high-throughput deep sequencing to identify functional sequences. The use of this method led to the identification of thousands of sequences that serve as translation enhancing elements (TEEs). Ongoing research in my laboratory is aimed at identifying the exact mechanism by which these TEEs function and analysis of the potential proteins that could be produced using this cap-independent method. In addition to gaining fundamental knowledge regarding cap-independent translation, my research also aims to use TEEs to boost protein production from potential viral-based vaccines, thereby increasing the effectiveness of these vaccines and their potential to improve human health.

Research projects

Project I:

Identification of mechanistic properties that drive human translation enhancing elements
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 will now analyze these sequences and explore 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.

Project II:

Using human translation enhancing elements to boost antigen production from vaccinia virus based vaccines
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.

SELECTED PUBLICATIONS

Altertoxins with potent anti-HIV activity from Alternaria tenuissima QUE1Se, a fungal endophyte of Quercus emoryi.
Bashyal BP, Wellensiek BP, Ramakrishnan R, Faeth SH, Ahmad N, Gunatilaka AA. Bioorg Med Chem. 2014 Nov 1;22(21): 6112-6.
doi: 10.1016/j.bmc.2014.08.039.

A leader sequence capable of enhancing RNA expression and protein synthesis in mammalian cells.
Wellensiek BP, Larsen AC, Flores J, Jacobs BL, Chaput JC. Protein Sci. 2013 Oct;22(10): 1392-8.
doi: 10.1002/pro.2325.

Genome-wide profiling of human cap-independent translation-enhancing elements.
Wellensiek BP, Larsen AC, Stephens B, Kukurba K, Waern K, Briones N, Liu L, Snyder M, Jacobs BL, Kumar S, Chaput JC. Nat Methods. 2013 Aug;10(8): 747-50.
doi: 10.1038/nmeth.2522

Inhibition of HIV-1 Replication by Secondary Metabolites From Endophytic Fungi of Desert Plants.
Wellensiek BP, Ramakrishnan R, Bashyal BP, Eason Y, Gunatilaka AA, Ahmad N. Open Virol J. 2013 Jul 26;7: 72-80.
doi: 10.2174/1874357920130624002.

Differential HIV-1 integration targets more actively transcribed host genes in neonatal than adult blood mononuclear cells.
Wellensiek BP, Ramakrishnan R, Sundaravaradan V, Mehta R, Harris DT, Ahmad N. Virology. 2009 Mar 1;385(1): 28-38.
doi: 10.1016/j.virol.2008.10.052.

Molecular characterization of the HIV-1 gag nucleocapsid gene associated with vertical transmission.
Wellensiek BP, Sundaravaradan V, Ramakrishnan R, Ahmad N. Retrovirology. 2006 Apr 6;3: 21.