|T H E N I H C A T A L Y S T||M A Y J U N E 2006|
ON THE ROAD TO DOCTORAL DEGREES: NIH GRADUATE STUDENTS
EMERGE FROM THEIR LABS TO REVEAL THEIR RECENT FINDINGS
by Fran Pollner
The Graduate Partnerships Program (GPP) is NIH's contribution to the training of graduate students who are working toward a degree in the biomedical sciences at accredited universities in the United States and abroad. The university partners provide the coursework and the degree, and, in some cases, research advisors; NIH provides the labs, NIH research mentors, and hands-on research training.
There are now about 370 students in the GPP, and that number will top 400 when the new students arrive this summer. The students come from more than 100 universitiesabout 62 percent based in the United States and 38 percent elsewhere.
The third annual GPP graduate student research symposium took place May 5. Seventy-six of the students presented posters; 11 gave talks on their research.
Judged on the basis of "organization, clarity, and scientific significance," 20 of the posters were designated "finalists." From this cohort, three were selected as winners (see footnote).
Following are brief reports on two of the 76 posters.
HARNESSING THE ANTITUMOR EFFECT OF AN IMMUNOSUPPRESSANT FOR LUNG CANCER PREVENTION
Now a fourth-year student in the graduate genetics program at George Washington University in Washington and already the holder of a master's degree in public health, Courtney Granville has been working in the NCI lab of Phillip Dennis for three years, drawn there, she says, by the lab's "emphasis on tobacco-related lung cancer and the environmental causes of disease in general."
Equally important is the "translational nature of the lab's research." The science, Granville says, "is very real and very applicable." She wants to focus her career on chemoprevention and can envision working in academia or a regulatory agency.
"Rapamycin, an inhibitor of mTOR, decreases tobacco carcinogen-induced lung tumorigenesis"
Courtney Granville, George Washington University, Washington, D.C., Graduate Program in Genetics
NIH research advisor: Phillip Dennis, investigator, Medical Oncology Branch, NCI-CCR
Granville's research project, which was one of 14 selected for oral presentation at the GPP Research Symposium, explored further the role of tobacco-activated mTOR in the induction of lung cancer, as well as the inhibition of mTOR in the prevention of lung cancer and the amelioration of existing tumors.
The Dennis lab had previously shown that tobacco components activate the Akt/mTOR pathway.
In the current project, the team treated mice that had been exposed to a specific tobacco carcinogen with rapamycin, an mTOR inhibitor that is also an immunosuppressant approved by the FDA to prevent post-transplantation graft rejection and to coat arterial stents.
Rapamycin works as an immunosuppressant by squelching T-cell proliferation and function, Granville noted; it has been studied in tumor models and found to shrink existing tumors.
In the current study, Granville and her colleagues showed that tobacco carcinogeninduced lung tumorigenesis depends on mTOR and that rapamycin-mediated inhibition of mTOR prevented the development of lung lesions in carcinogen-exposed mice. The action of rapamycin before the emergence of observable lesions had not previously been demonstrated, Granville noted.
This ability to suppress tumorigenesis "provides a rationale to test mTOR inhibitors in smokers at high risk for lung cancer," Granville wrote in her abstract. She noted in an interview, however, that the immunosuppressive action of rapamycin would necessarily inspire great caution in considering it as a preventive agent, even in heavy smokers.
That rapamycin might be useful as a cancer preventive was suggested, however, in a study reported last year: Transplant patients who received rapamycin exhibited a decreased incidence of de novo malignancies, compared with transplant patients who had received other immunosuppressive drugs.
Figuring out how to maximize rapamycin's antitumor effect while minimizing its immunosuppressive
effect would be a worthy pursuit for future studies, Granville said.
PARENTAL ALCOHOL USE REFLECTED IN BRAIN MEASUREMENTS OF ADULT ALCOHOLICS
The field of neuroscience, Gilman says, is "awesome." One of the 20 or so finalists among the 76 graduate students who presented posters at the GPP Graduate Student Research Symposium, Gilman is in her second year of doctoral training at Brown University in Providence. Eventually, she says, she would like to work at NIH or in academia.
"Influence of parental alcoholism on brain volumes in alcoholics"
Jodi Gilman, Brown University, Providence, R.I. Graduate Program in Neuroscience
NIH research advisor: Daniel Hommer, chief, Brain Electrophysiology and Imaging, Laboratory of Clinical and Translational Studies, NIAAA
Images of the brains of alcoholics pose general questions regarding cause and effect and particular questions regarding genetic versus environmental causes.
Jodi Gilman and her NIAAA co-workers aimed to tease out the effects of alcoholism and the influence of parental history on brain structure and function in adult alcoholics.
Study volunteers were alcoholics seeking inpatient treatment at the NIH Clinical Center. Sixty-four men and 27 women had no family history of parental alcoholism; 96 men and 60 women had at least one heavy-drinking or alcoholic parent.
Using MRI, the team measured intracranial volume (ICV), cerebral brain volume, and white and gray matter volume.
Consistent with reported findings in previous studies, the entire cohort of alcoholics had smaller-than- average brain volumes. Beyond that, however, the alcoholics with a positive family history had significantly smaller ICVs than those with unaffected parents, a finding not previously demonstrated.
Unlike the cerebral cortex, which is subject to alcohol-induced atrophy, ICV is a particularly intriguing measure, Gilman said, because it reaches its permanent size by about age 12 to 16. Factors operating during the time between conception and puberty, thereforenot the individual's alcoholismwould be in play.
"We have a lot more to study," Gilman noted, listing functional MRI studies; looking at the influence of family history on the size of different parts of the brain, such as the frontal lobe; looking more deeply at the cogitive and emotional impact of family history; analyzing the impact of age at drinking onset on measures; and, of course, "everyone is still looking for genetic factors."
The fact, however, that people have been looking for genetic factors for decades inclines Gilman to accord a greater role to environmental reasons to account for why children of alcoholics are at a fivefold increased risk of becoming alcoholics themselves.
The stress of growing up in an environment where heavy alcohol consumption is a fact of daily life might account, too, for the physical brain findings, she remarked.
only does stress affect brain growth and development in animals, she observed,
but there are studies showing that children subjected to abuse and other experiences
associated with post-traumatic stress disorder have reduced ICVs.
*At the end of the GPP poster day, three of the 76 graduate student poster presenters were declared winners. In alphabetical order, they are:
Kristina Buac, George Washington University graduate program in genetics, Washington, D.C., "Wireless, a novel ENU-induced allele of ErbB3 gene exhibiting neural crest defects distinct from the null allele." NIH research advisor, Bill Pavan, senior investigator, Genetic Disease Research Branch, NHGRI.
Daniel Spellman, New York University School of Medicine graduate program in structural biology, "Stable isotopic labeling of amino acids in cultured primary neurons for the study of protein turnover and neuronal signal transduction." NIH research advisor, Alfred Yergey, Head, Section on Mass Spectrometry and Metabolism, NICHD.
Honghong Zhu, Johns Hopkins University School of Public Health graduate department of epidemiology, Baltimore, "Secondhand smoke and breast cancer risk: a population-based prospective cohort study." NIH research advisor, Kenneth Cantor, senior investigator, NCI-DCEG.
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