Despite the widely recognized importance of kinases in human biology, a significant portion of the human kinome remains poorly characterized. A systematic means of identifying connections between understudied kinases and human physiology could have a transformative effect on human health. One approach is to leverage emerging genomic datasets and mine for associations between specific gene sets and diseases or clinical traits. However, the mechanisms by which variants contribute to the disease process are often unclear, especially in the case of understudied genes. Therefore, integration of complementary methods is required to frame these genes into biochemical pathways and to begin to understand the mechanisms by which they contribute to human physiology. To bridge this gap, we have integrated genetic information with blood levels of metabolites and proteins (~5,000 analytes) to begin to establish the genetic architecture of the human metabolome and proteome. As highlighted in the present proposal, our compendium of gene-analyte associations can also be leveraged for focused interrogations of specific gene sets to create biochemical signatures of metabolites or proteins ?downstream? of common or rare genetic variants. In this proposal, we will generate biochemical signatures of genetic variation in the understudied kinases (Aim 1). Theses biochemical signatures will highlight potential new metabolic pathways regulated by kinase biology that can then be validated and studied by genetic manipulation in model systems.
In Aim 2, we will use deep phenotyping studies in model organisms to illuminate the biological underpinnings of gene-analyte associations. Further, based on recent proof-of-concept findings, we will test the specific hypothesis that the poorly characterized kinase, CAMK1D, modulates triglyceride metabolism in vivo. Successful completion of these aims will provide opportunities to understand the biological functions of understudied kinases and will provide novel mechanistic insights into the biology they regulate. Further, this proposal will provide a strong foundation in the application of emerging ?multi-omics? approaches to a new investigator and will lay the groundwork for a subsequent R01 application to use this pipeline to study a range of understudied genes.
Kinases are enzymes that regulate every aspect of cellular activity. However, many human kinases remain poorly characterized. Here we systematically identify connections between these understudied kinases and the human biology they regulate through the integration of genomics, proteomics and metabolomics data.
