CAREER: Defining kinase-driven cellular response networks using single-cell genomics

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How a cell responds to stress is critical to its performance in biomedical applications. Modifying the response can dramatically improve treatment outcomes. For example, altering the response to chemotherapy could inhibit or reverse tumor growth. Altering the immune system response could reduce the need for vaccine development. Many of the key regulators of these responses are enzymes known as kinases. Several kinase inhibitors have proven successful in treating certain cancers. Utilizing genomic tools to identify which kinases control specific cellular stress responses is a core strategy in this project. Advancing equity and inclusion in the genomics field at various academic levels is another major objective. Introducing genomic technologies and analysis to high school students in the NY Bioforce program is another major thrust of this project. Collaboration with the University of Puerto Rico to develop short courses will also be undertaken.The goal of this project is to enable large-scale data-driven prediction of how genes alter cellular response. To this end, assays that extend single-cell genomics to a multiplex platform to map the effects of perturbations will be developed. The objective is to define the molecular changes that cells undergo in response to cellular stress and how those responses depend on the activity of individual kinases in the protein kinome. Information on kinase regulatory networks will be used to manipulate cellular response towards phenotypes of interest, such as treatment-sensitive cell fates. Methods to query these cellular responses must account for how even a seemingly homogeneous group of cells can display substantial heterogeneity in their response to cellular stress. The project leverages high-throughput single-cell genomic techniques to arrive at kinase regulatory networks that define the response of cells to genotoxic stress, immune-associated programs, and genetic redundancy driving dynamic changes induced by kinase inhibition.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.