The organization of cellular stress response networks and repair mechanisms

The Adamson lab studies the organization and function of molecular networks in human cells, with particular focus on understanding (a) how cells differentially leverage these networks to respond to stress and (b) how abnormal programs of stress response contribute to disease. We also develop and improve innovative technologies for genetics and cell biology, including those with potential therapeutic applications such as genome editing.

Stress response networks have traditionally been studied in bulk assays and thus have been described largely as dedicated pathways with stereotyped activation regimes. However, we know that these systems are deeply complex, with diverse sensory mechanisms and integrated subroutines controlling cell outcomes. This complexity helps maintain normal cell function in response to diverse perturbations. Problematically, it can also allow cells to survive pathogenic network dysregulation or enable abnormal adaptation to multicellular disease states. Therefore, understanding stress responses at a systems-level and from a functional perspective is critical. We use and develop innovative experimental technologies, including CRISPR-based functional genomics, single-cell RNA-sequencing, and genetic interaction mapping, to investigate molecular and genetic networks. These high-resolution techniques allow systematic mapping of network behavior across conditions. From this, we identify interesting behaviors, with special interest in context-dependent behaviors, and then, using more conventional genetics and cell biology approaches, characterize underlying mechanisms. Current efforts include investigating how cells mount tailored responses to endoplasmic reticulum stress and DNA damage.

Genome editing technologies that target programmable sequence changes to specific genomic loci have substantial potential for therapeutic applications. However, realizing the promise of these approaches will require improving their to-date limited specificity. We have recently pioneered methods to systematically investigate how synthetic mechanisms of genome editing, including CRISPR-based single-strand template repair and DNA base editing, interact with endogenous DNA repair networks. One goal of this work is to identify parameters that can be tuned to achieve optimal in vitro and in vivo editing outcomes.

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