Environmental Factor, October 2010, National Institute of Environmental Health Sciences
Council hears two science talks at fall meeting
By Eddy Ball
At the meeting of the National Advisory Environmental Health Sciences Council Sept. 1-2 (see related story (http://www.niehs.nih.gov/news/newsletter/2010/october/spotlight-council.cfm)), NIEHS once more honored the tradition of showcasing its science and giving members a welcome respite from the program reports. For its fall meeting, members enjoyed presentations by grantee Sven-Eric Jordt, Ph.D., and by NIEHS Principal Investigator Mike Resnick, Ph.D.
In 2006, Jordt(http://info.med.yale.edu/pharm/faculty/index.php?bioID=39) was selected as one of the first NIEHS Outstanding New Environment Scientist (ONES) awardees and is the principal investigator of a grant under the NIH CounterACT program administered by NIEHS. The next year, Jordt became the first NIEHS grantee to be honored with a Presidential Early Career Award for Scientists and Engineers (PECASE).
Resnick (http://www.niehs.nih.gov/research/atniehs/labs/lmg/cs/index.cfm) is head of the NIEHS Chromosome Stability Group and a veteran investigator with a long list of honors and outstanding publications (see this month's summary (http://www.niehs.nih.gov/news/newsletter/2010/october/science-intramural.cfm) of his most recent Paper of the Month). Resnick was honored as NIEHS Scientist of the Year in 2008, and since the inception of the "Best Paper of the Year" at NIEHS in 2003, his group has received this award for 2003, 2004, and 2007.
Jordt and Resnick are examples of NIEHS-funded investigators involved in basic research, with promising translational potential for treating and preventing human injury and disease.
TRP channels in chemical sensing and environmental disease
Jordt's work has its roots in his postdoctoral research on the mechanisms of transient receptor potential (TRP) channel receptors, which are part of an early warning system of sensory neurons activated during injury and chronic painful conditions. These receptors trigger tears, sneezing, neurogenic inflammation, pain, and respiratory constriction in the upper airway.
A series of important papers by Jordt's group over the past four years has uncovered the role of TRP channel activation, specifically TRPA1, in mammalian responses to noxious chemical and physical stimuli, such as cigarette smoke, tear gas agents, and chlorine. Recent work by the group has expanded investigations into the role of sensory neuronal ion channel activation in producing airway inflammation and hyperactivity in allergic asthma (see related story (http://www.niehs.nih.gov/news/newsletter/2009/july/science-jordt.cfm)).
In his work with wildtype and TRPA1 knockout mice challenged with ovalbumin, Jordt and his colleagues have experimented with a TRPA1 antagonist, HC-030031, that was found to be protective in exposure to noxious gases. The antagonist, they found, also gave wildtype mice the same protection as that enjoyed by the genetically modified mice against the asthmatic response, inhibiting eosinophil infiltration and preventing the development of airway hyperreactivity.
Jordt's recent work also addresses the TRPM8 cold-sensitive channel activated by menthol and may support efforts by public health advocates to end use of this anti-inflammatory agent in cigarettes.
The expanding universe of p53 targets
As the latest step in his basic research on genome stability, Resnick entered into an innovative Intramural Research Award collaboration last year (see related story (http://www.niehs.nih.gov/news/newsletter/2010/february/science-pritchard.cfm)) with two NIEHS clinical investigators, Michael Fessler, M.D., and Stavros Garantziotis, M.D.
In his Council presentation, Resnick reviewed his group's findings from research on budding yeast and human cells and the work that informs the new paper that Resnick, Fessler, and Garantziotis, along with Chromosome Stability Group members Daniel Menendez, Ph.D., and Maria Shatz, Ph.D., have recently submitted for publication - "The human Toll-like receptor (TLR) family is integrated into the DNA damage and p53 response network."
Resnick reviewed the tumor suppressor p53 as the "guardian of the genome" in its role as a sequence-specific transcription factor and master regulator of more than 200 genes and non-coding sequences in the human genome, and he described recent findings that greatly expand the p53 network of target genes. With his cross-disciplinary collaborations, Resnick is investigating the evolution of p53 networks, including ones that seem to be primate specific, and addressing what he calls "the dramatic synergy" of the estrogen receptor and p53 networks.
Studies of human primary lymphocytes from healthy volunteers have revealed p53 control of most human TLR genes and shed light on the mechanisms of p53 control and its involvement in variations in innate immunity.�� These findings will likely have potential implications in terms of better understanding individual susceptibility to environmentally linked diseases and for the advancement of personalized medicine.