We’re delighted to announce that the Lage Lab has been awarded a three year grant from the Simons Foundation Autism Research Initiative to to study the protein networks perturbed by genetics in autism. Kasper Lage is thrilled to join the community of Simons Foundation Investigators. The project will enable us to leverage and strengthen our current experimental work in the Stanley Center for Psychiatric Research at the Broad Institute and is a collaboration with Kevin Eggan’s lab in the Stanley Center and the Department of Stem Cell and Regenerative Biology, Harvard University.
For more about the Stanley Center at the Broad Institute click here
For more about Kevin Eggan’s Lab click here
For more about the Simons Foundation Autism Research Initiative click here
Proposal Abstract:
The recent explosion in genetics in autism spectrum disorders has revealed many genes likely to be involved in these debilitating disorders. These efforts have resulted in exciting glimpses of molecular pathways emerging from the data (e.g., chromatin remodeling and synaptic transmission). While such examples illustrate how genes linked to autism interact at the level of proteins to form networks involved in diverse areas of neurobiology, most of the identified genes do not fall into any well-defined cellular pathway and it is now clear that the biology also includes largely uncharted and incomplete networks that are probably unique to the human brain. This is a key bottleneck towards biological insight and therapeutic intervention. Here, we propose to overcome these challenges through an integrative approach that leverages recent genetic discoveries with large-scale proteomics experiments to derive human brain networks (of physically interacting proteins) perturbed by genetics in autism. This network will serve as an accelerator of functional insight from current and future psychiatric genetics data and it sits at the inflection point of transformative technology and data that have just become mature: First, we will capitalize on new unbiased genetic data to choose corresponding proteins (termed “index proteins” throughout the proposal) as the starting point of the network analysis. Second, we will exploit new proteomics technologies to map the tissue-specific quantitative interaction networks of these index proteins at high resolution. We believe that this network will be of broad value to interpret current and future studies in psychiatric genetics, and that it will immediately contribute to guiding therapeutic insight and intervention. Third, the proteomics experiments will be coupled to exciting progress in our ability to generate human neurons from induced pluripotent stem cells so that the interactions of index proteins are derived in a biologically meaningful cellular (and human) context. Fourth, we will experimentally follow up on discoveries from our analyses using reductionist neurobiological assays we have access to through collaborators. It is an important aspect of this application that we will establish a robust statistical methodology, which is currently lacking, for integrative analyses of experimental proteomics networks and genetic data that can be a model for others to use in any area of genetics in the future. Overall, the goal of this project is to leverage the genetic analyses to map, validate and follow up on the brain-specific cellular networks perturbed by genetics in autism. This will catalyze biological insight and inform future therapeutic opportunities.