RESEARCH
Cellular stress responses are ancient, highly conserved programs that enable cellular survival in harsh conditions. These powerful responses fundamentally rewire the cell’s expression of the central dogma, broadly altering translational, transcriptional, and metabolic activity. This is all well and good when stress responses are activated appropriately—but maladaptive activation of stress responses are a hallmark of a wide swathe of age-related diseases.
The decision to activate stress response is enacted by protein machinery that instigates the many diverse outcomes of stress response . In the Lawrence Lab, we are interested in understanding how these dynamic stress response machines enact the stress response. A key breakthrough, enabled by advances in structural biology, biochemistry, and machine learning, has been the ability to define and characterize how conformation of stress response machines encode stress response outcome. We exploit these advances to (1) map how cellular stimuli activate stress response machines and (2) program disease-relevant stress signaling states using structure and AI-guided design.
We are interested in these questions:
(1) how does cellular stress response machinery dynamically sense and respond to cellular metabolic state (see Project 1)?
(2) why does chronic activation of stress response selectively impair specific metabolically specialized cell types (see Project 2)?
Project 1: Mechanisms of cellular stress responsive decision-making
PROBLEM:
How does the stress response machinery sense cellular status and encode adaptive and maladaptive stress response states?
APPROACH:
We combine biochemical, cell biological, and structural methods to visualize stress response decision-making in space and time. For example, we build off of recent work demonstrating that the Integrated Stress Response (ISR), is carried out by a conformational change in the super-enzyme eIF2B. We are interested in questions like: How does eIF2B’s conformation dynamically response to cellular metabolic status? What metabolites can eIF2B sense?
Projects in this area can involve any combination of cellular biochemistry, cryo-EM, enzymology, and high-throughput methods including metabolomics and FLOW cytometry- based activity assays.
Project 2: Mechanisms of selective vulnerability to chronic stress in glia
PROBLEM:
Cellular stress pathways are gradually upregulated during normal aging, and are hyperactivated in the context of age-related neurodegenerative disease. For example, chronic activation of the Integrated Stress Response (ISR) drives learning and memory defects in a wide range of neurodegenerative contexts, from Alzheimer’s disease to hypomyelinating disorders. But rather than affecting all cells equally, chronic ISR seems to selectively impair only certain highly specialized cell types in the brain.
How does chronic stress signaling selectively impair glial cell function?
APPROACH:
Mounting evidence suggests ISR signaling impairs glial function by remodeling cellular metabolism, but we have lacked the tools to define the underlying cellular mechanisms. We are using structure and AI-guided design to engineer novel chronic stress signaling iPSC-based cellular models.
Projects in this area combine biochemical, functional genomic (CRISPR), and cell biological methods to define mechanisms via which chronic ISR signaling impairs glial function in in vitro and in vivo models.