Jun Shen
| T H E N I H C A T A L Y S T | M A Y – J U N E 2008 |
|
|
|
| P E O P L E |
RECENTLY TENURED
|
|
Jun Shen
|
Jun Shen received his Ph.D. in 1995 from
the University of Wisconsin at Madison. He did postdoctoral work at Yale
University in New Haven, Conn, and was a research assistant professor at New
York University and a senior staff investigator at the Nathan Kline Institute
in Orangeburg, N.Y., before joining NIMH as an investigator in 2002. He is
currently a senior investigator in the Mood and Anxiety Disorders Program,
NIMH.
My group studies brain chemistry
using, primarily, in vivo magnetic resonance spectroscopy (MRS) and
imaging. In vivo MRS allows
noninvasive detection of metabolic events and neurotransmission in the living
human brain. It offers a unique window into brain chemistry by providing
valuable biomarkers for various brain disorders. We develop in vivo MRS and
spectroscopic imaging techniques and apply them to brain studies.
Whereas proton MRS measures static
concentration of important brain chemicals (for example, GABA, the major
inhibitory neurotransmitter in the CNS), 13C
MRS allows determination of dynamic metabolic fluxes by introducing exogenous 13C-labeled substrates. For example, the
flux between neuronal glutamate and astroglial glutamine (an indicator of
presynaptic glutamate release) can be determined by measuring the kinetics of 13C label incorporation into glutamate and
glutamine from 13C-labeled glucose or
the glia-specific substrate acetate.
Converging evidence suggests that
hyperglutamatergic activity and GABAergic dysfunction play important roles in
the neurobiology and treatment of depression and other mood disorders. For
instance, we found abnormal GABA levels in the prefrontal cortex of patients
with major depressive disorder but normal levels in depressed patients in
remission.
To understand the interactions
between GABAergic and glutamatergic systems, we first studied the effect of
altered brain GABA level on focal excitability of rat brain. Using proton MRS
to measure GABA and functional magnetic resonance imaging to measure neuronal
activation, we found that GABA level is negatively correlated with the extent
of functional neuronal activation. Next, we used 13C MRS to measure the flux from neuronal glutamate to astroglial
glutamine and back in the rat brain, infusing 13C-labeled
glucose in the first instance and 13C-labeled
acetate in the second. In both cases, we found that increased brain GABA level
attenuates the trafficking of neurotransmitter glutamate between glutamatergic
neurons and astroglia. The results of our animal studies provide a
glutamat-ergic mechanism of action for GABA-elevating drugs that may contribute
to their mood-stabilizing effects.
The quantification of GABA synthesis
and glial uptake of neurotransmitter GABA has been controversial due to rapid
post-mortem GABA anabolism. We developed the first in vivo 11.7 Tesla MRS
techniques using a vertical 89-mm bore magnet. 11.7 Tesla is still the highest
field strength at which in vivo MRS of brain has been successfully attempted
and enables spectral separation between 13C-labeled
GABA and glutamate in the proton spectra.
Using our 11.7 Tesla MRS methods, we
performed the first in vivo measurement of GABA turnover from 13C-labeled glucose and acetate. Our
results demonstrate that neuronal glucose, not glial glutamine, is the major
metabolic precursor of GABA and that the intercompart-mental GABA-glutamine
cycle is a minor flux for clearance of released neurotransmitter GABA.
In addition to measuring static
concentrations and dynamic fluxes, MRS has also been used to measure the
activity of certain enzymes in vivo using magnetization transfer. The
phenomenon of in vivo enzyme-specific magnetization transfer was discovered for
creatine kinase and ATP exchange reactions in the late 1970s using 31P MRS. Since then, no new enzyme-specific
magnetization transfer effects had been found in vivo until our recent
discovery of magnetization transfer effect catalyzed by aspartate
aminotransferase, lactate dehydrogenase, malate dehydrogenase, and carbonic
anhydrase.
Our
discoveries have extended the scope of in vivo 13C MRS to include enzyme activities. We hope that by using
hyperpolarized 13C imaging techniques
we can generate in vivo enzyme activity images. 
ON TENURE TRACK by Caroline Small, OITE communications intern, and Eric Schaffer, OIR communications intern Joseph Hibbeln, a psychiatrist and lipid
biochemist by training, describes himselfas an investigator attempting to
translate basic neuroscience on the omega-3 essential fatty acids docosahexaenoic
acid (DHA) and eicosapentaenoic acid (EPA) into direct clinical applications.
He is acting chief of the Section on Nutritional Neuroscience, Laboratory of
Membrane Biochemistry and Biophysics, NIAAA.
Eleven years after originating a
hypothesis that omega-3 deficiencies increase the risk of depression, violence,
and suicide, Hibbeln co-authored omega-3 treatment recommendations for the
American Psychiatric Association in 2006.
His work also forms the core of a
2008 United Kingdom Parliamentary Inquiry Report that recommends increasing
omega-3 intake in school children, pregnant women, patients with major mental
disorders, and prison populations.
Hibbeln’s collaborative clinical
trials with investigators in Kuopio, Finland; Dublin, Ireland; the Brooklyn,
N.Y., VA; Columbia University in New York; the University of Arizona; and the
University of Cincinnati have demonstrated the efficacy of omega-3s in reducing
suicidal thinking and depression among Irish subjects with a history of
deliberate self-harm, reducing anger and anxiety among polysubstance abusers,
treating depression during and after pregnancy, and reducing the severity of
bipolar symptoms in children.
He theorizes that adequate intakes of DHA, in particular,
might reduce the violence, depression, and anxiety common among alcoholics,
whose brain stores of DHA are depleted. Underlying mechanisms appear to include
serotinergic and dopaminergic depletion, increased neural vulnerability to
apoptosis, excessive transcription of corticotropin-releasing hormone, and
accompanying dysregulation of the hypothalamic-pituitary-adrenal axis, he
said.
During fetal development, the
nervous system is especially vulnerable to omega-3 deficiencies caused by
limiting seafood intake during pregnancy. Thus, Hibbeln tested the efficacy of
the 2004 EPA/FDA advisory for fertile or pregnant women to consume less than 12
ounces of seafood a week. He sought to determine whether the risk from
nutritional deficiency from avoiding seafood was greater than the risk of exposure
to trace levels of methylmercury.
Hibbeln traveled frequently from NIH
to collaborate with investigators at the University of Bristol. He found that
when maternal consumption of seafood was at or below the limits of the 2004
advisory, the children were more likely to have low verbal IQ and suboptimal
behavioral and social development. Paradoxically, the advisory was intended to
reduce these harms.
Hibbeln has reported links between
increasing rates of homicide, violence, and major depression potentially attributable
to changes in the U.S. and international food supply. Such changes include
lower consumption of seafood and higher consumption of competing omega-6
essential fatty acids from seed oils.
Hibbeln said he hopes “to nurture
the field” with extensive collaborations, especially internationally, and is
translating his epidemiological studies into clinical trials to reduce violence
among prisoners in the Delaware prison system and, at NIH, is designing
metabolic diets to selectively lower omega-6 intake.
He is developing protocols to prevent and treat depression, suicide, and post-traumatic stress disorder among military personnel by restoring nutritional adequacy.—C.S.
|
||
Mihaela Serpe is the newest investigator in the Laboratory of Gene Regulation and Development at NICH D, where she works at
untangling the molecular mechanisms of cellular signaling that guide the
embryonic and later development of fruit flies.
Serpe started out as a biochemist at
the University of Bucharest, but developed a passion for signaling while
earning her Ph.D. at SUNY-Buffalo in stress sensing and cellular response to
stress. That passion took her to the University of Minnesota-HHMI, where she
started to examine the ways cells encode and interpret signals about their
location in the developing embryo.
“I became fearless,” she says of her
time in Minnesota, where she started to work with fruit flies and sometimes did
experiments in worms, frogs, and zebrafish to better understand the class of
signaling molecules known as transforming growth factor–beta (TGF–b).
The TGF-b superfamily of growth and differentiation factors is one of the
largest classes of signaling molecules. TGF-bs control many biological processes including patterning, from
deciding which side of an embryo is dorsal to finessing the crossveins in a
fly’s wing.
Serpe’s work aims at understanding
the intricate regulation of these factors by a handful of secreted molecules,
such as Crossveinless-2 (Cv-2), which recently attracted her attention by its
ability to both facilitate and impede the action of some TGF-b signals—the bone morphogenetic proteina (BMPs).
In a 2008 paper, she showed that
Cv-2 binds to BMPs, to the cell
surface, and to the BMP receptor and can either antagonize BMPs or guide them
to receptors.
To understand how molecules like
Cv-2 can modulate BMP gradients and shape the fly wing, Serpe has teamed up
with computer scientists at the University of Minnesota to create mathematical
models. Through constant comparison between the wet bench data and
computational models, she’s been able to hunt more effectively for the
mechanisms of signal interactions.
It’s this precise refinement in the
developmental message that fires Serpe’s passion for cellular communication.
“The style of the language” is her main focus, “rather than the letters used,”
she says. For her, it’s in the subtle shadings of the proteins repertoire that
medical applications begin to be seen.
She envisions the development of
efficient therapies, including the speedy repair and strengthening of damaged
bones, arising from an understanding of the molecular mechanisms responsible
for localizing and stabilizing BMP signaling in fruit flies.
|
