From intracellular sensors to systemic resilience: Reframing the biology of stress.

The biological consequences of chronic stress and trauma are complex, influencing multiple systems and contributing to the development of psychiatric disorders such as MDD and PTSD. Yet, the underlying molecular mechanisms that confer susceptibility in some individuals but resilience in others remain incompletely understood. To help close these knowledge gaps, my work centers on glucocorticoid signaling as a core mechanism underlying stress-related adaptations. This includes the glucocorticoid receptor (GR), its co-chaperones FKBP5 and FKBP4, and regulatory partners such as SKA2. Through a combination of genetic, viral, pharmacological, and transcriptomic approaches, my lab has delineated how these molecules influence HPA axis feedback, fear-related learning, and stress recovery. Recently, we identified a novel, GR-independent role for SKA2 in regulating secretory autophagy, a non-lytic autophagy pathway involved in vesicular cargo release, including cytokine secretion in microglia. These findings established a mechanistic link between intracellular stress signaling and neuroinflammatory responses. In a parallel line of research, we are investigating how chronic stress alters the gut microbiome composition and function, and how these changes impact behavior. Our aim is to harness dietary and probiotic interventions to restore homeostatic balance and enhance stress resilience. By integrating molecular neuroscience with immune and microbiome research, my long-term goal is to build a comprehensive, systems-level model of stress vulnerability and resilience. This approach holds promise for identifying novel biomarkers and therapeutic targets that support mental health and resilience across the lifespan.