Karolinska Institute, Stockholm, Sweden
2007-2009
Principal Investigator: Uno Lindberg, Ph.D.
Redox, profilin, and tropomyosins in the control of the MF System
Behaviour and differentiation of cells are steered by cell:cell communication,
and by the interactions cells have with soluble or insoluble
components in their surroundings. Transmembrane proteins,
growth factor receptors, adhesion proteins, and ion channels,
play a central role in this communication. Their signals
to the interior of the cell activate the motile machinery
of the cell and increase the rate of proliferation. Motile
activity is generated by a highly dynamic, and well organized,
weave of actin microfilaments (MF) connected to the inside
of the cell membrane. Although there has been great progress
in our understanding of the physiological importance of
the MF-system, many aspects are still unclear. It has been
reported that generation of reactive oxygen species (ROS;
H2O2) in cells might control the MF-system, and the roles
of ROS in disease, including autism and cancer, is emerging
fields of research. An understanding of the role of hydrogen
peroxide (H2O2) in the regulation of proteins of the MF-system
(actin, profilin, and tropomyosin) is urgently needed.
Dendritic spines at postsynaptic contacts of excitatory neurons depend
on polymerization of actin, and synaptic deficiencies and
neuronal migration defects have been identified as causes
of hippocampal and amygdalar dysfunctions linked to autism.
Furthermore, tumorigenicity is highly correlated with changes
in the organization and activity of the MF-system. H2O2
is essential to growth factor-induced signaling, since ROS
quenching abolishes its effects, and PTEN, a tumor suppressor
protein, linked to the MF-system is directly controlled
by oxidation. Inactivation of PTEN results in uncontrolled
motility. Lindberg's group has recently shown that actin,
like profilin and tropomyosin, is sensitive to oxidation.
With the present project they hope to contribute to the
understanding of the function of the MF-system in normal
and dysfunctional cells.
The
Uno Lindberg Research Group, Karolinska Institute
Massachusetts Institute of Technology, Cambridge, MA
2009
Principal Investigator: Damon Page, Ph.D.
5-HT2x Receptor as a Candidate Regulator of Social Circuitry and Therapeutic Target for ASD
Do the genes of autism influence the development of brain circuitry involved in social behavior, and if so, then how does this happen? A specific aim of this research is to test the hypothesis that the social behavioral abnormalities present in Pten haploinsufficient mice arise from the dysregulation of 5-HT2cR and from the resulting disruptions in the circuitry underlying social behavior. To test this hypothesis, Dr. Page plans to examine whether a drug that antagonizes 5-HT2cR activity, SB 242084, is capable of modifying social approach behavior in Pten haploinsufficient mice. He will carry out testing using a three-chamber social approach apparatus. In parallel, Dr. Page will use the expression of an activity-regulated gene product (cFos) to test the hypothesis that one or multiple areas of the brain involved in social behavior (prefrontal cortex, nucleus accumbens, amygdala, VTA, parventricular nucleus) are differentially activated upon exposure to social cues in Pten haploinsufficient mice. If data obtained from these experiments are consistent with these hypotheses, Dr. Page will use SB 242084 to test whether antagonism of 5-HT2cR in Pten haploinsufficient mice can normalize patterns of neural activity in response to social cues. If these data are inconsistent with these hypotheses or inconclusive, he will then test the hypothesis that the Oxytocin system may be disrupted in Pten haploinsufficient mice. The Oxytocin system is normally involved in pro-social and social recognition behaviors, and Dr. Page has pilot data that suggests that expression of Oxytocin is reduced in Pten haploinsufficient mice. He will test whether administration of Oxytocin can modify social approach behavior in Pten haploinsufficient mice, making use of the same approach described for SB 242084.
Laboratory of Mriganka Sur
Princeton University, Princeton, NJ
2008-2010
Principal Investigator: David W. Wood, Ph.D.
Development of Bacterial Screens for ASD-Associated Compounds (Co-funded
with the Lurie Family Foundation)
This project seeks to accelerate the identification of specific
chemicals that may be associated with autism spectrum disorder
(ASD) by taking previously identified ASD-associated proteins,
and cloning these proteins into a simple bacterial biosensor
system. The sensor is designed such that growth of the resulting
bacterial cells will depend on the conformation and activity
of the cloned ASD-associated protein. The simplicity of
the bacterial system will then facilitate the high-throughput
screening of suspect chemicals for any effects on the cloned
ASD-related protein. If effects are found (based on the
resulting bacterial growth rates), then it is likely that
those chemicals will have similar effects on that ASD-associated
protein in human patients. Thus these bacterial biosensors
will act as a highly simplified model for small pieces of
ASD in humans, allowing studies of specific biochemical
compounds and interactions that are associated with the
disorder.
David Wood
Vanderbilt University, Nashville, TN
2007-2008
Principal Investigator: Pat Levitt, Ph.D.
MET Receptor Tyrosine Kinase and Autism Spectrum Disorders
(Co-funded with the Simons Foundation)
MET is a protein that mediates cell functions involved in building
brain architecture, and in gastrointestinal repair and immune
responses. Based on their discovery of a variant of the
MET gene that is associated with autism spectrum disorder
(ASD), Dr. Levitt and colleagues hypothesize that alterations
in MET function contribute to the brain-based and medical
conditions that characterize individuals with ASD. They
also hypothesize that environmental factors compound genetic
risk by disrupting MET expression. The functional MET variant,
which decreases expression of the gene approximately 2-fold,
more than doubles the risk of ASD. The investigators will
determine whether the variant defines individuals with specific
medical and behavioral co-occurring conditions. Subjects
with ASD and co-occurring medical conditions, such as GI
or immune disorders will be studied through ASD medical
clinics at Vanderbilt and Massachusetts General Hospital
. The investigators will determine which individuals carry
the ASD-associated MET variant, and correlate expression
of the MET protein in blood immune cells and when available,
in gut biopsies. These subjects and those from the AGRE
and Simons collections will be subdivided using available
behavioral and social scales to determine if the MET variant
is found more prevalently with certain traits. Finally,
the investigators will examine how the MET variant in cells
responds following exposure to common environmental toxins, such as dioxin and fertilizers that interfere with gene
expression. This research program will lead to better means
for diagnosing and treating subgroups of ASD patients, and
determine how gene-environment may play a role in increasing
ASD risk.
Vanderbilt
Kennedy Center for Research on Human Development
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