|
|
Ross
B. Mikkelsen, Ph.D., Professor,
pursued his graduate education in biology at the University of California, Santa Barbara (1968 – 73).
Since his radiobiology postdoctoral fellowship at Tufts University, Dr. Mikkelsen has been a leading scientist on membrane ion
gradients, calcium homeostasis, reactive oxygen/nitrogen homeostasis, and
their roles in regulating signal transduction pathways and cellular
responses to cytotoxic drugs, oxidative stress
and ionizing radiation. Telephone: (804) 828-8778
e-mail:
rmikkels@vcu.edu
|
|
|
Laboratory of Ross Mikkelsen
Redox homeostasis mechanisms and cellular radiosensitivity
Dr. Ross Mikkelsen initially demonstrated that
ionizing radiation in the clinically relevant dose range stimulates
significant transient changes in cytosolic [Ca2+]
in all epithelial tumor cell lines examined. These studies have been
extended to analyses of mechanisms by which cells sense radiation and
metabolically produced reactive oxygen and how resulting signals are
amplified and translated into cellular responses. Dr. Mikkelsen’s
laboratory demonstrated that one cytoplasmic
mechanism involves a mitochondrial oxidative event that is propagated via a
Ca2+ dependent reversible mitochondrial permeability transition. A
consequence is the activation of constitutive, Ca2+ dependent nitric oxide synthases. The generation of NO provides a mechanism by
which cells can modulate signal transduction pathways including MAPK and cGMP-dependent kinases and
the redox sensitivities of different
transcription factors. NO also reacts with superoxide
and thus provides a mechanism for buffering localized increases in cytotoxic, mutagenic superoxide/hydrogen
peroxide. Because NO is relatively stable and lipophilic,
NO generation potentially provides a mechanism by which an oxidative event
in one cell can be signaled to adjacent cells. Current studies are
examining Cys S-nitrosylation
and Tyr nitration as protein modification
mechanisms by which NO activates cellular responses to oxidative events and
the role of NO synthases in reducing oxidative
base damage as a consequence of radiation exposure and metabolic activity.
|
|
