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CELLULAR AND MOLECULAR MECHANISMS - PAST GRANTS



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.


Karolinska Institute


Lurie Family Autism Center / Massachusetts General Hospital
2011


Principal Investigator: Andrew W. Zimmerman, M.D.

A Trial of Sulforaphane in Autism

Despite intensive research efforts, neither prevention nor treatment of underlying mechanisms in autism is currently possible. In a recently published study, Dr. Zimmerman and colleagues confirmed anecdotal observations that behavioral symptoms in autistic children improve during episodes of fever. The cellular mechanisms underlying the effects of fever in autism remain to be clarified, however it is likely that heat shock proteins are involved. Dr. Zimmerman and his group hypothesize that in autism, enhancement of under-expressed genes and induction of the cellular stress response proteome, including heat shock proteins, will occur in response to treatment with sulforaphane. Mounting evidence shows that sulforaphane, a derivative of cruciferous vegetables (and therefore of low toxicity), defends cells against stresses by upregulating a network of cytoprotective genes that defend against oxidation, inflammation and mitochondrial dysfunction. All of these processes have been described in autism, in which multiple genes appear to be involved, with mutations that are not lethal but cause marked dysfunction, especially in the central nervous system. To date, specific gene mutations account for only 10-15% of patients with autism. Positive effects of fever occur in from 38 to 83% of patients with autism. Sulforaphane, as both oral and topical broccoli sprout extracts, penetrates the CNS and is well tolerated. It has been shown to be bioavailable to nerve cells and accumulates in the brain with various routes of administration. Dr. Zimmerman and his group propose a Phase I/II study of sulforaphane in 45 young adult males with autism, 13-30 years of age. They will measure a core feature of autistic spectrum disorders: social communication deficits. Cellular effects of sulforaphane will be measured in lymphocytes during treatment. The trial’s primary objectives are to answer whether treatment administered within a specified dose range is safe, treatment administered within a specified dose range is well tolerated by young autistic males, there is evidence of a measurable effect on behavioral symptoms, there is evidence that treatment within the specified range has observable activity affecting social communication, and key cellular biomarkers support the hypothesized mechanism.


Massachusetts Institute of Technology, Cambridge , MA
2004-2008

Principal Investigator: Damon Page, Ph.D.


Toward an Understanding of the Developmental Basis of Brain Dysfunction in Autism: Molecular and Cellular Mechanisms of Cortical Region and Network Formation

The cerebral cortex is made up of anatomically and functionally distinct regions and past evidence has suggested that abnormal formation and activity of certain areas may be involved in autism. This research will investigate morphological and functional regionalization of the mammalian cerebral cortex in normally developing mouse models to understand how the development of the cerebral cortex may be disrupted in autism. The use of diverse tools available in mice will enable us to understand how genes cooperate with one another and with extrinsic signals to build regions and functional circuitry in the cerebral cortex. This research will provide a basis for understanding how processes may be disrupted in individuals with autism, and should contribute to better diagnosis and treatment of this condition.

Damon Page


Massachusetts Institute of Technology, Cambridge, MA
2009-2010

Principal Investigator: Damon Page, Ph.D.

MAPK3 as a Chr 16p11.2 Autism Candidate Gene

he chromosomal region of 16p11.2 has emerged from genetic screening in humans as a significant susceptibility locus for ASD. This interval contains 25 genes; however, the link between these genes and the symptoms of ASD is not clear. Dr. Page’s research seeks to bridge this gap in our understanding by investigating the role of candidate genes from the 16p11.2 region in the development of brain and behavior, using the mouse as a model system. The first candidate gene he will focus on is MAPK3. Dr. Page selected this gene as a candidate for the following reasons: 1) He previously found that ERK, the Drosophila homologue of MAPK3, influences regionalized growth in the embryonic brain by controlling proliferation of specific populations of neural stem cells in response to activation of the receptor tyrosine kinase EGFR in these cells (Page, 2003), 2) MAPK3 is know to act in the PTEN/PI3K pathway to influence a variety of cellular processes relevant to growth (Cully et al., 2006). Dr. Page has found that haploinsufficiency for Pten leads to brain overgrowth as well as social behavioral deficits (Page et al., 2009), two phenotypes relevant to ASD. And, 3) MAPK3 acts in several additional pathways that have been implicated in ASD pathogenesis, including: Serotonin (Launay et al., 1996), Oxytocin (Blume et al., 2008) and IL-6/immune signaling (D'Arcangelo et al., 2000). Dr. Page’s studies indicate that Pten intersects with these pathways in the developing brain. Thus, the possibility that MAPK3 might act as an intermediary across these pathways is one worth exploring. As an initial investigation of the function of Mapk3 in ASD-relevant endophenotypes, Dr. Page will make use of assays of social approach behavior and brain growth.

Damon Page


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 W. 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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