The Gregory lab is involved in several group-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) is implicated in the disease. This work is being achieved through close collaboration with the lab of Dr Mariano Garcia Blanco and Dr Lisa Barcellos at University of California, Berkeley and involves assessing T cell signaling of IL7 in MS patients, understanding the mechanism of IL7R splicing (2), and the construction of an IL7R mouse model of the disease. Dr Gregory is also Principal Investigator of the MS-MURDOCK study. The study is currently developing 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.
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 (3,4,5) . 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.
Neural Tube Defects:
NTDs encompass a variety of aberrant developmental phenotypes, including spina bifida and anencephaly (6,7). Dr. Gregory is collaborating with Drs. Allison Ashley-Koch, Janee Van Waes (Creighton University) and Ron Riley (USDA) to identify the genetic causes of NTD through environmental exposure to fumonisin in Guatemala (8). The Gregory lab is also using next-generation sequencing to identify causal mutations in genetically loaded NTD families, and DNA methylome profiling techniques to establish the role of environmentally labile epigenetic marks in the development of NTDs within discordant monozygotic twins.
Chiari malformation is the downward displacement of the cerebellar tonsils into the central nervous system causing a variety of neurological symptoms including headaches, fatigue, dizziness, nausea, and, in severe cases, paralysis. The Gregory lab is collaborating with Dr Allison Ashley-Koch to identify the genetic causes of the disorder, i.e. whether herniation of the tonsils results from a cramped posterior fossa or via tethering of the spinal cord (9,10).
Recent CDC estimates suggest that autism affects more than one in 68 children in the US. Dr Gregory's group is using several approaches to not only understand the genetic and epigenetic mechanisms underlying autism, but also how children can be treated to improve their symptoms, and the events at the time of birth that may lead the development of the disorder. 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. Dr Gregory is also a PI within the SOARS consortium headed by Dr Lin Sikich at the University of North Carolina. This exciting new clinical trial will assess 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 epigenetic and expression biomarkers of oxytocin response (11). Finally, the Gregory lab is collaborating with Dr Marie Lynn Miranda at the University of Michigan and Dr Chad Grotegut at the Duke University Medical Center to understand how events at birth, particularly induced and or augmented births, may lead to the development of autism (12).
Fuchs Endothelial Corneal Dystrophy:
FECD a slow progressing degenerative disease of the cornea that usually affects both eyes, is slightly more common in women than in men, and usually impacts visual acuity in the 50s and 60s. Dr Gregory is collaborating with Dr Yi-Ju Li and Dr. Gordon Klintworth to understand the genetic basis of the disease. The Duke FECD team has accumulated an FECD collection of over 1400 individuals and is considered one of the largest such collections in the country (13,14).
Osteoarthritis (OA) is the most prevalent form of arthritis world-wide. According to the recent Global Burden of Disease 2010 Project, OA is a leading cause of disability globally and the fastest increasing major health condition. The Gregory lab is currently pursuing two collaborations to understand the development and progression of OA. The first is with Duke researchers Drs. Virgina Kraus and Elizabeth Hauser to profile the epigenetic and transcriptomic changes associated with primary tissue in the development of osteoarthritic knees while the second collaboration with Dr Fashid Guilak is aimed at identifying the epigenetic mechanisms associated with diet induced changes of mouse stem cells in the development of obesity and OA.