The Gregory lab is involved in several lab-based and collaborative research projects that focus on identifying the genomic, genetic, and epigenetic underpinnings of complex disease.
In 2007 Dr Gregory and his collaborators identified the first MS gene outside of the MHC (interleukin 7 receptor, IL7R) to be associated with the disease (Gregory et al, 2007 Nature Genetics). A continuing collaboration with Dr. Mariano Garcia Blanco (UTMB) has subsequently shown that the DExD-Box Helicase 39B gene (DDX39B) not only regulates alternative splicing of IL7R but it is also genetically associated with MS in a rarely proven epistatic interaction (Galarza-Muñoz et al, 2017, Cell). Most recently, Drs. Gregory and Garcia-Blanco have further established the novel splicing mechanisms of IL7R around the evolutionary conservation of polypyrimidine tracts in IL7R that influence U2AF2 binding and U2 snRNP recruitment to IL7R exon 6 that harbors MS associated C allele (Schott et al, 2021, RNA).
Dr. Gregory is Principal Investigator of the MURDOCK_MS study that developed a ~1,000 patient multiple sclerosis collection that has been used to identify multi-omic biomarkers to facilitate reclassification of the disease (Cote et al 2019, Multiple Sclerosis and Related Disorders), and the use of ultra-high sensitivity protein assays to plot the trajectory of disease development in a cohort of primary progressive MS patients (under review Giarraputo et al, Journal of Neuroimmunology).
Dr. Gregory is also exploring the efficacy of a novel hydroxyl-cholesterol (HC) treatment of remyelination in MS with Drs. Eric Benner (Duke, Pediatrics), Mari Shinohara (Duke, Immunology), and Glenn Matsushima (UNC-CH, Microbiology and Immunology). In this transformative study, Dr. Gregory and his colleagues are trying to understand the cellular mechanisms in which HCs trigger the differentiation of neural progenitor cells into oligodendrocyte progenitor cells (OPCs) and/or OPCs into oligodendrocytes, the cell that is critical for triggering remyelination in MS. Early data provides exciting evidence of remyelination in the context of a demyelinating pre-clinical model of MS.
Recent CDC estimates suggest that autism affects more than one in 68 children in the US. The Gregory lab is using genetic and epigenetic approaches to understand the mechanisms driving core deficits associated with autism at developmental and therapeutic levels via oxytocin treatment in pre-clinical and human trials with Dr. Lin Sikich. In collaboration with Dr. Sheryl Moy (UNC, Psychiatry) and Dr. Yong-Hui Jiang (Yale, Medical genetics), Dr. Gregory's lab is exploring the mechanisms of oxytocin response in a clinical trial of autistic children, to refine the epigenetic regulation of the oxytocin receptor (OXTR), and to understand the molecular underpinnings of oxytocin effects and societal interaction in an animal model of autism. The findings will provide valuable insight into the mode of action of oxytocin response in specific regions of the brain that will be applicable to clinical trials of oxytocin treatment in numerous psychosocial phenotypes, including autism.
Dr. Gregory’s lab is also pioneering the development of single cell ‘omic profiling and spatial transcriptomic and in situ sequencing approaches towards understanding the mechanism of disease development and progression. Through collaborative research and as Director of the Molecular Genomics Core, Dr. Gregory has facilitated research of more than 60 single cell and spatial projects at Duke, including his own studies into oxytocin response in preclinical models of autism (above), HC treatment response in neural stem cells (above), the progression of Alzheimer’s disease with Drs. Jerry Wang and Dianne Cruz , and in the development of brain tumors with Dr. David Ashley in Duke’s Brain Tumor Center.
Single cell and spatial technologies to understand disease mechanisms.