CELLULAR AND MOLECULAR MECHANISMS  
Below are descriptions of the Cellular and Molecular Mechanisms grants that are currently active. To view a list of past grants in this area, please click on the link below.

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.


The Uno Lindberg Research Group, Karolinska Institute



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.

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

 
Copyright © 2005 Nancy Lurie Marks Family Foundation