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 age-related and neurodegenerative diseases.

The decision to activate stress response is coordinated by dynamic protein machines that instigate the many diverse outcomes of stress response. But how do these machines sense and respond to stress? A key breakthrough has been enabled by recent advances in structural biology: the demonstration that conformation of stress response machines encode stress response outcomes. We will build on these advances to (1) map how cellular metabolic stimuli activate stress response machines and (2) define molecular mechanisms of stress-linked neurodegenerative diseases by modeling stress signaling states via genome editing and structure-guided design in iPSC-derived glia.

Ongoing Projects:

  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 (that resembles a butterfly flapping its wings) in the large, multimeric enzyme complex 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 a combination of cellular biochemistry, cryo-EM, enzymology, and high-throughput methods including metabolomics and FLOW cytometry- based activity assays.

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 glial 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, and use them as ideal biochemical systems in which to define how signaling is remodeled in response to stress.

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.