2009 Biomedical
Research Collaboration Award
Memphis, TN, December 05, 2009 --
The Hartwell Foundation officially
announced the second winners of
a
Biomedical Research
Collaboration Award,
which provides
funding to expand the frontiers of early-stage,
innovative, and cutting-edge applied biomedical research
through special collaboration.
Charles E. Glatt MD,
Ph.D., Weill Medical College of Cornell University and
Jian Zuo, Ph.D., St Jude Children's Research Hospital, will receive $291,173
in combined direct cost over three years to pursue their
proposed research for “Identification of Predisposing
Factors in Childhood Depression: Using a Conditional
Knock-In Mouse to Generate the Implicated Risk and
Protective Variants of the Serotonin Transporter Gene.”
The Hartwell
Foundation currently funds both researchers: Dr. Zuo is
a 2006
Hartwell Investigator, while Dr. Glatt is a 2007
Hartwell Investigator. Cornell University and the
St Jude Children's Research Hospital are both
among The Hartwell Foundation’s
2009 Top Ten Centers of
Biomedical Research.
Serotonin is a universal signaling molecule involved in
nerve communication and the serotonin transporter (SERT)
protein is a major regulator of serotonin function.
Notably, SERT is an important candidate gene for
depression, because the most commonly used
antidepressant medications all act by inhibiting the
activity of this protein.
In pioneering research, Dr. Glatt has identified a
variant in the gene responsible for SERT (polymorphism
rs3813034) that alters how the gene is expressed. The
polymorphism affects the balance between the two different molecular
forms of serotonin transporter mRNA and leaves them
distributed differently in the brain. One form appears
to increase risk for depression while the other form
protects against depression. The variant is a single
nucleotide polymorphism that occurs in the
polyadenylation signal for the distal form of SERT mRNA.
It occurs in the signal sequence for processing the
protective form in human brain and reduces the signal’s
effectiveness, thereby lowering the amount of the
protective form relative to the risk form. Using a
conditional knock-in mouse to generate the implicated
risk and protective variants of the serotonin
transporter gene, Glatt and Zuo plan to relate the
changes induced during early biological development to
the onset of depression.
“As a Hartwell Investigator, Jian Zuo is a leader in
creating genetically engineered conditional knock-in
mice. The Collaboration Award will provide us a unique
opportunity to advance a new strategy to move the
behavioral genetics of depression from a descriptive to
a mechanistic approach. In the absence of an appropriate
mouse model, understanding the genetic changes that
predispose to depression in childhood would require
access to living, human brain tissue,” said Dr. Glatt.
The Glatt-Zuo collaboration will advance the current
field of depression genetics because the animal model
will enable controlled experiments to identify critical
developmental periods with risk for depression and
identification of windows of opportunity for clinical
interventions. Surprisingly, the collaboration may also
provide insight in how to regain hearing, as in their
early discussion of mutual interests, it became apparent
to both investigators that the auditory cells
responsible for hearing express SERT and use serotonin
to regulate cellular function.
“Together, we propose to design and create a mouse model
that expresses only the high-risk form of a major
candidate gene for depression, which can also be induced
to re-express the protective form at specific
developmental stages. In collaborating, we discovered an
unexpected benefit from mutual interest in each other’s
research focus,” said Dr. Zuo.
The collaboration between Glatt and Zuo began when they
met at The
Hartwell Foundation 2008 Annual Meeting. The
availability of Hartwell video conferences and mentoring
fostered their progress. Early in their collaboration,
they recognized that auditory cells responsible for
hearing express SERT and use serotonin to regulate
cellular function. At that time, Dr. Zuo began to wonder
if alterations in SERT could change the survival of the
auditory hair cells, which in his original Hartwell
proposal he had proposed to regenerate following the
loss of hearing. Discussions between investigators
prompted many literature searches that went beyond the
molecular biology of depression, elevating intriguing
possibilities about how drugs that alter the function of
SERT can restore vision in the brain after it is lost,
how serotonin aids in cell survival and regeneration,
and how drugs that block SERT cause hearing loss in
children.
Depression is a disabling neurodevelopmental condition
that often has its onset in adolescence. A major portion
of the risk for depression in children and adolescents
is due to genetic factors that an individual inherits
from his or her parents, which are complex and poorly
understood. The identification of genetic risk factors
for depression would allow early identification of
at-risk youth and aggressive intervention that could
alter the course of illness. However, human genetic
studies of depression have only identified minor risk
factors that are not consistently replicated and thus
not clinically useful. Genetic studies have focused on
depression as a clinical rather than a biological entity
and thus, the molecular effects contributed by genetic
risk factors have not been specifically matched to the
biological processes that contribute to depression.
Children undergoing chemotherapy and children overdosed
with antibiotics often lose their hearing. This is
mostly due to the loss of the auditory sensory cells in
the inner ear. Humans and other mammals cannot replace
damaged such sensory cells; however, chickens, fish, and
amphibians can, by dividing neighboring cells derived
from the same parental cells and adopting their sensory
cell characteristics. Recent studies have highlighted
the critical role of certain cell-cycle regulators to
regenerate functional sensory cells in mammalian inner
ears. The feasibility of manipulating key proteins in
neighboring supporting cells to regenerate damaged
sensory cells is in progress using animal models. Many
factors will need to be studied, and genetic
manipulations in such models offer unprecedented
advantages.
|
|
_small.JPG)
2007 Hartwell
Investigator Charles E. Glatt, MD, Ph.D.,
Weill Medical College of Cornell University
2006 Hartwell Investigator
Jian Zuo, Ph.D.,
St Jude Children's Research
Hospital
HOME
|
