Date of Graduation


Document Type


Degree Type



School of Medicine


Microbiology, Immunology, and Cell Biology

Committee Chair

Gordon Meares

Committee Member

Christopher Cuff

Committee Member

Jennifer Franko

Committee Member

Michael Schaller

Committee Member

James Simpkins

Committee Member

Edwin Wan


Neurological and neurodegenerative diseases are heterogenous and devastating diseases with limited therapeutic options and no cures. The broad, long-term goal of this project was to elucidate therapeutic targets for neurodegenerative conditions that attenuate damaging inflammation while leaving the beneficial immune response intact and avoiding broad immunosuppression. Inflammation and the accumulation of misfolded proteins are associated with a wide variety of neurological diseases. Here, we have examined how the accumulation of misfolded proteins shapes inflammatory signaling in the glial cell population astrocytes. Astrocytes are the most populous cell in the central nervous system (CNS) and provide physical and trophic support to the CNS. Proper astrocyte function is paramount for a healthy brain. Recent evidence indicates endoplasmic reticulum (ER) stress and inflammation are linked. ER stress occurs when the protein folding capacity of the cell is overwhelmed, resulting in the initiation of the unfolded protein response (UPR) to regain homeostasis. However, unresolved UPR activation leads to cell death and aberrant inflammation. Further, astrocytes are relatively resistant to ER stress-induced cell death. We have found that UPR activation in astrocytes activates JAK1-dependent inflammatory gene expression. Canonical JAK1 signaling is initiated by ligand binding of a cytokine receptor that results in Signal Transducers and Activators of Transcription (STAT)-dependent inflammatory gene expression. Using RNA sequencing of primary murine astrocytes, we have demonstrated that JAK1 regulates approximately 10% of ER stress-induced gene expression. However, we found JAK1 initiates different gene expression based on the activating stimulus. In response to ER stress, JAK1 regulates a distinct subset of gene expression that we hypothesize does not rely on JAK1-dependent phosphorylation of STATs. Instead, we have described a noncanonical role for JAK1 in response to ER stress that utilizes the transcription factor activating transcription factor (ATF) 4. ATF4 is expressed in response to ER stress and other types of cell stress. We demonstrate here that JAK1 and ATF4 coimmunoprecipitate, suggesting a physical interaction between these two proteins. Further, we showed via ChIP-seq that JAK1 is required for ATF4 to bind transcription start sites in promoter regions. Here, we have demonstrated a mechanism by which JAK1 regulates ER stress-induced gene expression in astrocytes in a noncanonical mechanism. Future directions of this project will focus on understanding the physiological consequences of this pathway in vivo in models of neuroinflammation.

Embargo Reason

Publication Pending