Dr. Gregory's autism research focuses on four areas:
Tissue specific Epigenetic profiling: The identification of mutations within the methyl CpG binding protein 2 gene, MECP2, and their causal relationship with Rett syndrome has highlighted the relationship between aberrant DNA methylation and neurodevelopment. DNA methylation and imprinting, heritable changes in gene regulation that do not involve changes in an individuals genetic code, are recent and exciting realms of autism research. Dr Gregory has carried out genome-wide methylation profiling of a set of 14 temporal cortex DNAs from individuals with autism and 14 sex and age matched controls to establish patterns of genome methylation in a tissue type that has been targeted as being one of the regions of the brain that functions aberrantly in individuals with autism. Results from these analyses continue to be analyzed and are hoped to provide ground breaking data in the normal profile of a specific region of the brain, in addition to identifying differentially regulated genes between individuals with and without autism. The results will provide the basis for a larger study involving methylation profiles of other regions of the brain, in addition to functional analysis of candidate genes from the pilot study.
Genetics: Duke has a well-established infrastructure for ascertainment, clinical evaluation and specimen collection of individuals with autism and their family members for genetics research. For a number of years, Dr G Robert Delong (Professor Emeritus in the Division of Pediatrics) and Dr Gordon Worley (Professor in the Department of Development Medicine & Pediatric Rehabilitation) have been intimately involved with genetics research at Duke, not only via patient ascertainment but also by contributing their many years of experience diagnosing and treating individuals with autism spectrum disorders. These efforts resulted in the recruitment of DNA from ~800 individuals from ~120 families. Drs. DeLong and Gregory are currently pursuing a hypothesis in which families, whose parents have been diagnosed for psychosocial disorders OCD and Bipolar and whose children have autism, are currently being exome sequenced to identify DNA mutations which cumulatively result in autism in the offspring.
The 15q11-13 hypothesis: Genome copy number, genetic linkage and parent of origin effect studies have consistently implicated human chromosome 15q11-13 in the development of autism and autism spectrum disorders. Additionally, chromosome rearrangements and epigenetic imprinting defects within 15q11-13 are known to cause Prader-Willi and Angelman’s syndromes, which have autism-like symptoms. Although these studies have investigated the association between aberrant epigenetic marks within 15q11-13 and autism they have primarily focused on individual genes or imprinted loci. They have carried out a novel approach to identify aberrant genomic and epigenetic signatures within human 15q11-13 in a large multiplex autism family. Autism specific signatures will be replicated in other autism families from their cohort that display similar patterns of comorbid inheritance. The data from these modalities are currently being analyzed.
Oxytocin as a treatment: Dr. Gregory is collaborating with Dr. Lin Sikich at Duke in an NIH funded project whose aim is to establish the safe and efficacious use of oxytocin nasal spray in the treatment of children with autism. The project, which will recruit 300 children from five sites across the US, will assess the children’s response to treatment using clinical measures of pro-social response, however, Dr. Gregory’s role is to develop molecular (gene expression and epigenetic) predictors of efficacy. Samples will be sent to the Gregory lab throughout the five years of the grant and will be tested to identify genes and pathways that are implicated in responders and non-responders.
Association of birth induction/augmentation with autism: Dr. Gregory and collaborators Drs. Marie-Lynn Miranda and Chad Grotegut recently published a high profile paper identifying an association of birth induction/augmentation with the development of autism. The association, which continued after accounting for many traditional risk factors in autism (maternal and gestational age and events at birth) provide an intriguing prospect however, Dr. Gregory and his colleagues emphasized that more research must be carries out to the establishing the exact factors that might be causal of the association. A grant proposing to access more detailed clinical information and a prospective collection of a birth cohort is currently in development. Dr. Gregory is also pursuing possible collaborations to measure levels of oxytocin (a drug used as part of standard practice to induce and augment births) in the cord blood spots of mothers that have/not had induced births.