David A. Ornelles, PhD

David A. Ornelles, Ph.D., Associate Professor

Dr. Ornelles received a Bachelor’s Degree in Electrical Engineering from the University of Hawaii. He attended graduate school at MIT where he received a Ph.D. in Biochemistry in 1987. Following a postdoctoral fellowship in molecular virology at Princeton University, Dr. Ornelles joined the faculty of WFSM in the Department of Microbiology and Immunology in 1993.

SYNOPSIS OF AREA OF INTEREST:

  1. Cellular restrictions imposed on adenovirus replication. We study the molecular basis by which the E1B-55K and E4orf6 proteins promote viral gene expression and overcome a cell-cycle-linked restriction imposed on adenovirus replication.
  2. Rational development of adenovirus for cancer therapy. The E1B-55K mutant virus is used to treat cancer even though the basis for its selectivity remains unknown. We seek to understand how the E4orf1 and E4orf3 proteins of adenovirus dictate the oncolytic nature of adenovirus and apply this information to the development of an improved oncolytic agent.
  3. DNA alterations associated with leukemia. Adenovirus has the power to elicit mutations in a hit-and-run fashion. We discovered that the leukemia-associated RUNX1 gene suppresses adenovirus replication. We seek to understand how RUNX1 suppresses virus replication and to determine if adenovirus infection of lymphocytic cells can contribute to the development of mutations associated with childhood leukemia.

DETAILED AREA OF INTEREST: Products of the adenovirus E1B and E4 genes act in concert to promote efficient expression of viral genes, to block the export of cellular mRNA from the nucleus, and to inactivate key host cell proteins that regulate cell growth and DNA repair. Mutant adenoviruses that cannot express the E1B-55K (55K) gene replicate most efficiently in cells that are rapidly dividing. Consequently, 55K-mutant adenoviruses are used to treat cancer even though the basis for their selective growth in cancer cells remains poorly understood.

Research on the E4 region of adenovirus has shed light on the tumor-selective nature of the 55K-mutant virus. Surprisingly, the E4orf1 protein suppresses late viral gene expression at the level of translation and limits the oncolytic efficiency of the 55K-mutant adenoviruses.

Deletion of the highly conserved E4orf3 gene in the 55K-mutant background gives rise to a double-mutant virus that replicates very poorly but kills certain human tumor cells with stunning efficiency. This double-mutant virus is unable to block host cell protein synthesis and fails to suppress the cellular DNA-damage response. This leads to the hypothesis that tumor cells with a heightened intrinsic level of DNA damage signaling will be especially susceptible to killing by this virus.

Another line of study, seeking to identify cellular factors targeted by the 55K and E4orf6 proteins, has identified RUNX1 as a candidate cellular gene. Interestingly, RUNX1, also known as AML1, is the most frequently disrupted gene in acute childhood leukemia. This line of study may identify an important regulator of immune and bone cell development as an important cellular target for adenovirus with potentially far-reaching implications for this apparently mild human pathogen. 

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Institute for Regenerative Medicine

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