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Interagency Autism Coordinating Committee (IACC)
Autism Research Database
Office of Autism Research Coordination (OARC)
 
Project Element Element Description

Project Title

Project Title

Behavioral and physiological consequences of disrupted Met signaling

Principal Investigator

Principal Investigator

Levitt, Pat

Description

Description

A number of risk genes for autism spectrum disorders have been identified, thanks to the intensive efforts of the Simons Foundation and other genetic consortia. This is just the beginning, however. A major goal of future research is to translate these genetic findings into a more in-depth understanding of how such risk, combined with environmental factors, disrupts the formation of brain architecture that leads to autism. This information is essential to designing better prevention, diagnostic and intervention strategies for the disorder. To that end, Pat Levitt, of the University of Southern California, is leading a collaborative effort by four laboratories to understand the functional implications of mutations in the autism risk gene MET, which codes for a receptor that is involved in the wiring up of important brain circuits. The researchers' previous study of three large collections of families with members with autism found a mutation in MET that more than doubles the risk for autism and reduces the amount of MET protein in the brains of people with the disorder. Three other research laboratories, using five different family collections around the world, have reported similar findings regarding MET as an autism risk factor. What's more, basic research in mice has shown that altering MET expression leads to problems in the formation of synapses — the junctions between neurons — which ultimately affects the ability of the cells to communicate with each other to process complex information. Levitt's team is working on clinical follow-up studies to determine the correlation between the MET mutation and disrupted brain and gastrointestinal functions in autism, a project also supported by the Simons Foundation. To understand why this gene may be a key risk factor for autism, Levitt and colleagues are investigating how the MET gene controls the development of synapses in circuits that control social and emotional behaviors and learning. In addition, Levitt and his colleagues will investigate the impact of a 'double hit' — a genetic mutation of MET, combined with exposure to a common pollutant that by itself negatively impacts developing brain architecture. This is being done by using genetic tools and new methods for measuring neuron activity in key brain circuits that include the cerebral cortex, a structure that is responsible for complex functions, such as processing social and emotional information. Their experiments will test the popular hypothesis that in autism, local and long-range connections in the brain do not assemble properly, leading to the core behavioral features of the disorder. The team of scientists are performing a number of studies. The development of new complex cognitive tests in mutant mice are being led by Larry Rothblat (George Washington University). Darryl Hood (Meharry Medical College) is leading the efforts involving prenatal exposure to polyaromatic hydrocarbons, a common pollutant that appears to have a negative impact on the long-term expression of both MET and another key protein, SP4, that can control MET expression. Advances in the local and long-distance circuit analyses in MET mutant mice are being led by Gordon Shepherd (Northwestern University), who has already demonstrated hyperconnectivity in local circuits. The research findings from this basic research program, the continuing clinical studies, and the additional genetic replication in new family collections, strongly support MET as a biologically and genetically relevant risk factor for autism.

Funder

Funder

Simons Foundation

Fiscal Year Funding

Fiscal Year Funding

800000

Current Award Period

Current Award Period

2009-2012

Strategic Plan Question

Strategic Plan Question

Question 4: Which Treatments And Interventions Will Help?

Strategic Plan Objective

Strategic Plan Objective

Green dot: Objective has greater than or equal to the recommended funding. 4SB. Standardize and validate at least 20 model systems (e.g., cellular and/or animal) that replicate features of ASD and will allow identification of specific molecular targets or neural circuits amenable to existing or new interventions by 2012. IACC Recommended Budget: $75,000,000 over 5 years.

Project Link

Project Link

Behavioral and physiological consequences of disrupted Met signaling (External web link)

Institution

Institution

University of Southern California

State/Country

State/Country

California

Project Number

Project Number

137273

Federal or Private?

Federal or Private?

Private

Received ARRA Funding?

Received ARRA Funding?

No

History/Related Projects

History/Related Projects

Behavioral and physiological consequences of disrupted Met signaling | 400000 | 2009 | 137273
Behavioral and physiological consequences of disrupted Met signaling | 400000 | 2012 | 137273
Behavioral and physiological consequences of disrupted Met signaling | 800000 | 2011 | 137273

 
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