The Gregory lab is involved in several lab-based and collaborative research projects that set out to identify 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 to be associated with the disease (1). The finding forms the basis of ongoing functional research to identify the mechanism by which the cytokine receptor (IL7R) and ILR are implicated in the disease. Dr. Gregory's lab is assessing T cell signaling of IL7 in MS patients, understanding the mechanism of IL7R splicing (2), and construction of an IL7R mouse model of the disease in collaboration with Dr. Mariano Garcia Blanco (UTMB). Dr. Gregory is Principal Investigator of the MS-MURDOCK study. The study has developed a ~1,000 patient multiple sclerosis collection that is independent of subtype with the aims of understanding the mechanisms associated with MS development and progression, and the generation of multi-omic biomarkers to facilitate reclassification of the disease. Finally, Dr. Gregory is using a mouse model of MS, experimental autoimmune encephalomyelitis (EAE), to understand the molecular mechanisms of disease development and efficacy of novel drugs. The Gregory lab is exploring the dynamics of mRNA and miRNA expression during EAE course using next generation sequencing approaches to elucidate the changes and interrelationships of gene function during EAE development and recovery. These data will provide the baseline for evaluating the mechanism of novel cyclotide drug function in collaboration with Dr. Christian Gruber (University of Brisbane). (3), and hydroxyl-oxysterols with Drs. Eric Benner (Duke, Pediatrics) and Mari Shinohara (Duke, Immunology).
Recent CDC estimates suggest that autism affects more than one in 68 children in the US. The Gregory lab is using independent approaches to not only understand the genetic and epigenetic mechanisms underlying autism, but also how children can be treated to resolve their symptoms. Dr. Gregory is project PI in the SOARS-B consortium headed by Dr. Lin Sikich of Duke University's Center for Autism and Brain Development. This exciting new clinical trial is assessing the efficacy of nasally delivered oxytocin to ameliorate some of the core deficits of autism. The Gregory lab's role in the consortium is to develop genetic and epigenetic predictors of oxytocin response and to assess the long term effects of drug exposure on these modalities (4). In collaboration with Drs. Sheryl Moy (UNC, Psychiatry) and Dr. Yong-hui Jiang (Duke, Pediatrics), Dr. Gregory's lab has recently been awarded an NIH grant to explore the mechanisms of oxytocin response in an animal model of the disease, to extend the epigenetic profiling of SOAR-B responders, and to refine the epigenetic regulation of the oxytocin receptor (OXTR). The findings of this grant will provide valuable data for the mode of action of oxytocin response in specific regions of the brain that will applicable to clinical trials of oxytocin response in numerous psychosocial phenotypes, including autism. Finally, together with Professor Emeritus of Pediatrics Dr. G. Robert Delong, Dr. Gregory is investigating how epigenetic factors within a multigenerational family can lead to the development of the disorder and how the identification of compound genetic risk factors in psychosocial families by exome sequencing may lead to the development of autism.
It is estimated that every one in four deaths in the US is attributable to heart disease and the health burden is believed to be greater than $100 billion annually. Dr. Gregory is collaborating with Drs. Svati Shah, Bill Kraus, and Elizabeth Hauser to identify the genetic architecture of the disease using Duke's unique CATHGEN cohort via GWAS and candidate gene association studies, metabolomic profiling with Dr. Chris Newgard, and transcriptomic and epigenomic approaches (5,6,7) . The latter, profiling the methylome of cardiovascular disease, also forms the basis of collaboration with cardiologists Drs. Svati Shah, Asad Shah, and G. Chad Hughes to identify DNA methylation and gene expression differences during bi- and tricuspid aorta development.
The Gregory lab is involved in a number of high risk high reward projects to identify the modalities of disease development. In collaboration with Dr. Chris Newgard, the Gregory lab is profiling gene expression changes in pancreatic islets under the regulation of Pdx and Nkx in a rat model of diabetes using next generation RNA-, ChIP-Seq and single cell expression profile approaches; while a collaboration with Drs. Fashid Guilak (Wash. U) and Dianne Little (Duke, Orthopedics) is aimed at identifying the epigenetic mechanisms associated with diet induced changes of mouse stem cells in the development of obesity and OA.