This project is one of four being proposed as part of the UCSD Autism Center of Excellence. One major goalof this study is to identify, in postmortem brain tissue, distinct gene expression profiles of autism that canimplicate risk genes for this highly heritable disorder. A second major goal is to identify, in circulating bloodcells, a validated gene expression profile of autism that can be developed as a diagnostic tool to improve itsidentification and early treatment. Although autism is recognized as having a substantial genetic component,its biological basis remains unknown. Due to its high heritability, much research has focused on identifyingcandidate genes that influence the disorder; however, progress has been slow. In part, this may beattributable to the 'single-marker' approach adopted in most prior efforts, since the etiologic complexity andheterogeneity of autism-spectrum disorders invariably thwart classification schemes relying on a singledimension to differentiate affected and unaffected children. To move beyond this single-marker approach, amajor objective of the proposed project is to validate suspected risk genes for autism (e.g., genes in theapoptosis, neurogenesis, and Drosophila wingless homolog [wnf] pathways), but also to find new candidategenes by observing patterns of expression of the entire human transcriptome in eight distinct brain regions.The lack of etiologic understanding of autism has also precluded the development of biologically baseddiagnostic strategies. As such, the diagnosis relies solely on observable behaviors emerging during the firstyears of life. Yet, the advantages of a more efficient biologically based diagnostic tool for autism arenumerous, and as such, another major objective of this study is to develop biologically based markers forautism. To accomplish these objectives, we will pursue five specific aims as follows: 1) Identify ubiquitousand region-specific disruptions in brain gene expression in autism; 2) Identify blood-based predictivebiomarkers of early-onset autism; 3) Identify blood-based predictive biomarkers of autism treatmentresponse; 4) Prioritize and verify the differential expression of top candidate genes in postmortem brain andperipheral blood; and 5) Integrate the results of this project with other projects within the Center. Theattainment of the :
specific aims outlined above will serve to validate several groups of risk genes for autism,identify a new set of potential risk genes, and validate peripheral blood-based biomarkers of the disorder, allwhile determining the specificity of these effects relative to other developmental disorders and to normaldevelopment. The identification of risk genes for autism should facilitate the development of noveltherapeutics, while the eventual development of a biological marker system for autism would greatlyenhance the efficiency of current diagnostic methods, and it likely would facilitate the search for additionaletiologic factors in the disorder.
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