The Ferguson lab seeks to define how MAPK8IP3 disease causing mutations affect the ability of the MAPK8IP3/JIP3 protein to act as a scaffold that interacts with and organizes the functions of other cellular proteins. These efforts have recently been guided by the use of Alphafold, a powerful AI-based tool for protein structure predictions. This video shows a model of a dimer of 2  MAPK8IP3/JIP3 proteins colored red and blue respectively. The locations of selected disease causing mutations have been highlighted within this model.

We are sponsoring Dr. Swetha Gowrishankar Assistant Professor in the Department of Anatomy and Cell Biology at The College of Medicine at The University of Illinois Chicago.  Her initiative is focused on evaluating efficacy of candidate compounds for rescuing lysosome defects in MAPK8ip3 KO iNeurons.

 The Gowrishankar Lab investigates the cellular changes in neurons resulting from loss of JIP3/MAPK8IP3 as well as de novo MAPK8IP3 mutations. Using human iPSC derived neurons as well as mouse models the Lab examines how organelle distribution (lysosomes, mitochondria and Golgi), axon specification and development are altered under these conditions. 

The results thus far have led the Gowrishankar Lab to focus on how MAPK8IP3 mutations alter neuronal polarity including axon initial segment integrity. Using an unboased approach of compartment-specific proteomics that was recently validated on the lab’s KO model, the Gowrishankar Lab intends to identify unanticipated changes in axons of the mutant cultured neurons. The lab uses the mouse models to determine physiological consequences of the mutations starting with health and survival. The Gowrishankar Lab will extend the results from cultured neurons to the mouse model to determine if there is cell type specificity as well as age-specific effects to the cellular changes arising from the MAPK8IP3 mutations. Lastly, the Gowrishankar Lab will examine the physiological consequences arising from cellular changes that have been observed.

The Yu Lab has demonstrated that MAPK8IP3 RNA processing is naturally inefficient, creating opportunities to turn the gene on or off in different cell types, or boost gene expression with ASOs. The Yu Lab has identified several RNA processing inefficiencies in the MAPK8IP3 locus in fibroblasts, astrocytes and iPSC-derived neurons and developed antisense oligonucleotides that increase correctly spliced MAPK8IP3 transcripts in all cell types. The Yu Lab also demonstrated significantly increased protein levels in fibroblasts and astrocytes.

Figure 1. Summary of experimental models used in the Yu Lab to study MAPK8IP3 mutations

The Yu Lab has successfully generated brain organoids from MAPK8IP3 R578C/+ iPSCs (and isogenic controls) and MAPK8IP3 M543del, allowing us to model brain development in multiple cell lineages (Figure 2). Organoids morphologically developed as expected and they expressed neural and neuroprogenitor markers tested by immunohistochemistry and gene expression analyses. Further QC steps included generation of single cell RNAseq data to confirm expression of relevant marker genes and demonstrate reproducible cell type proportions. MAPK8IP3 organoids exhibit abnormal gene signatures that provide leads for development as candidate biomarkers.

Figure 2. MAPK8IP3 and control organoids are shown at different days of differentitation.

Previous Research Work with Dr Roger Davis

Dr. Roger J. Davis is an Investigator of the Howard Hughes Medical Institute and is the H. Arthur Smith Professor and Chair, Program in Molecular Medicine at the University of Massachusetts Medical School. He received his initial training as a student at Cambridge University.  He also trained as a Damon Runyon Cancer Research Foundation fellow with Michael P. Czech at the University of Massachusetts Medical School.  He subsequently joined the faculty of the University of Massachusetts Medical School and was a founding member of the Program in Molecular Medicine.

Dr. Davis’ studies of signal transduction mechanisms led to the molecular cloning of the first human stress-activated MAP kinase, the cJun NH₂-terminal kinase (JNK).  Subsequent studies defined the molecular structure of the JNK pathway, including the identification of upstream and down-stream pathway components and scaffold proteins.  This signaling pathway is activated in response to many pathological / physiological stimuli and is implicated in inflammatory diseases (e.g. arthritis), cancer, stroke, heart disease, and diabetes.  The overall goal of Dr. Davis’ research is to understand the molecular basis for these diseases and to design novel therapeutic strategies.