Simon Gregory

Overview:

My principal area of research involves elucidating the molecular mechanisms underlying multi-factorial diseases. My lab is primarily interested identifying the complex genetic factors that give rise to multiple sclerosis, autism and cardiovascular disease. We are using targeted approaches to identify differential methylation of the oxytocin receptor gene (OXTR) in individuals with autism, and applying these data to an NICHD funded ACE award, SOARS-B, to assess long term use of oxytocin nasal spray to improve social reciprocity in 300 children with autism, and for which we are developing e/genetic and transcriptomic predictors of response and effects of long term drug exposure. My MS laboratories at Duke University and the David H Murdock Research Institute (DHMRI) are using cell signaling and immune cell flow sorting to establish the role of IL7R signaling in the development of MS; we have developed three novel mouse strains to induce EAE susceptibility and to investigate allele and splicing specific effects of IL7R in these novel MS models; I am PI of the MURDOCK-MS collection, a cross sectional MS cohort of ~1000 MS patients that will provide the basis for genetic, genomic and metabolomic biomarker identification of MS disease development and progression. I am also Director of the nascent Duke Center for Research in Autoimmunity and MS within the Duke Department of Neurology.

Positions:

Professor in Neurology

Neurology, MS & Neuroimmunology
School of Medicine

Research Professor in Molecular Genetics and Microbiology

Molecular Genetics and Microbiology
School of Medicine

Member of the Duke Cancer Institute

Duke Cancer Institute
School of Medicine

Member of Duke Molecular Physiology Institute

Duke Molecular Physiology Institute
School of Medicine

Education:

B.A.Sc. 1990

RMIT University (Australia)

Ph.D. 2003

Open University, Milton Keynes (U.K.)

Grants:

Bioinformatics and Computational Biology Training Program

Administered By
Basic Science Departments
Awarded By
National Institutes of Health
Role
Mentor
Start Date
End Date

Candidate Genes and Longitudinal Disability Phenotypes

Administered By
Center for the Study of Aging and Human Development
Awarded By
National Institutes of Health
Role
Co-Mentor
Start Date
End Date

Social Relationship Qualities as Predictors of Health & Aging from Adolescence thru Midlife

Administered By
Psychology and Neuroscience
Role
Co Investigator
Start Date
End Date

Dynamic Control of Innate Antiviral Immunity in Skin Homeostasis and Inflammation

Administered By
Dermatology
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Characterizing the (epi)genetics of oxytocin response in clinical and animal models

Administered By
Duke Molecular Physiology Institute
Awarded By
National Institutes of Health
Role
Principal Investigator
Start Date
End Date

Publications:

The TFAP2A-IRF6-GRHL3 genetic pathway is conserved in neurulation.

Mutations in IRF6, TFAP2A and GRHL3 cause orofacial clefting syndromes in humans. However, Tfap2a and Grhl3 are also required for neurulation in mice. Here, we found that homeostasis of Irf6 is also required for development of the neural tube and associated structures. Over-expression of Irf6 caused exencephaly, a rostral neural tube defect, through suppression of Tfap2a and Grhl3 expression. Conversely, loss of Irf6 function caused a curly tail and coincided with a reduction of Tfap2a and Grhl3 expression in tail tissues. To test whether Irf6 function in neurulation was conserved, we sequenced samples obtained from human cases of spina bifida and anencephaly. We found two likely disease-causing variants in two samples from patients with spina bifida. Overall, these data suggest that the Tfap2a-Irf6-Grhl3 genetic pathway is shared by two embryologically distinct morphogenetic events that previously were considered independent during mammalian development. In addition, these data suggest new candidates to delineate the genetic architecture of neural tube defects and new therapeutic targets to prevent this common birth defect.
Authors
Kousa, YA; Zhu, H; Fakhouri, WD; Lei, Y; Kinoshita, A; Roushangar, RR; Patel, NK; Agopian, AJ; Yang, W; Leslie, EJ; Busch, TD; Mansour, TA; Li, X; Smith, AL; Li, EB; Sharma, DB; Williams, TJ; Chai, Y; Amendt, BA; Liao, EC; Mitchell, LE; Bassuk, AG; Gregory, S; Ashley-Koch, A; Shaw, GM; Finnell, RH; Schutte, BC
MLA Citation
Kousa, Youssef A., et al. “The TFAP2A-IRF6-GRHL3 genetic pathway is conserved in neurulation..” Hum Mol Genet, vol. 28, no. 10, May 2019, pp. 1726–37. Pubmed, doi:10.1093/hmg/ddz010.
URI
https://scholars.duke.edu/individual/pub1366848
PMID
30689861
Source
pubmed
Published In
Hum Mol Genet
Volume
28
Published Date
Start Page
1726
End Page
1737
DOI
10.1093/hmg/ddz010

Whole blood sequencing reveals circulating microRNA associations with high-risk traits in non-ST-segment elevation acute coronary syndrome.

BACKGROUND AND AIMS: Although circulating microRNA (miRNAs) have emerged as biomarkers predicting mortality in acute coronary syndrome (ACS), more data are needed to understand these mechanisms. Mapping miRNAs to high-risk traits may identify miRNAs involved in pathways conferring risk for poor outcome in ACS. We aim to investigate the relationship between circulating miRNAs and high-risk traits in non-ST-segment elevation acute coronary syndrome (NSTE-ACS). METHODS: Whole-genome miRNA sequencing was performed on RNA extracted from whole blood of 199 patients with NSTE-ACS. Generalized linear models were used to test associations of miRNAs and 13 high-risk clinical traits, including the Global Registry of Acute Coronary Events (GRACE) score, a widely validated risk score for mortality in NSTE-ACS. RESULTS: There were 205 nominally significant miRNA-risk factor associations (p < 0.05) observed. Significant associations occurred most frequently with chronic heart failure (HF) (43 miRs), GRACE risk score (30 miRs), and renal function (32 miRs). In hierarchical cluster analysis, chronic HF and GRACE risk score clustered most tightly together, sharing 14 miRNAs with matching fold-change direction. Controlling for a false discovery rate of 5%, chronic HF was significantly associated with lower circulating levels of miR-3135b (p < 0.0006), miR-126-5p (p < 0.0001), miR-142-5p (p = 0.0004) and miR-144-5p (p = 0.0007), while increasing GRACE risk score inversely correlated with levels of miR-3135b (p < 0.0001) and positively correlated with levels of miR-28-3p (p = 0.0002). CONCLUSIONS: Circulating miRs clustered around two powerful traits for mortality risk in NSTE-ACS. MiR-3135b, which was under-expressed in chronic HF and increasing GRACE risk score, and miR-28-3p, which has no known association with cardiovascular disease, warrant further investigation.
Authors
Wang, A; Kwee, LC; Grass, E; Neely, ML; Gregory, SG; Fox, KAA; Armstrong, PW; White, HD; Ohman, EM; Roe, MT; Shah, SH; Chan, MY
MLA Citation
Wang, Alice, et al. “Whole blood sequencing reveals circulating microRNA associations with high-risk traits in non-ST-segment elevation acute coronary syndrome..” Atherosclerosis, vol. 261, June 2017, pp. 19–25. Pubmed, doi:10.1016/j.atherosclerosis.2017.03.041.
URI
https://scholars.duke.edu/individual/pub1250557
PMID
28437675
Source
pubmed
Published In
Atherosclerosis
Volume
261
Published Date
Start Page
19
End Page
25
DOI
10.1016/j.atherosclerosis.2017.03.041

Pregnancy continuation and organizational religious activity following prenatal diagnosis of a lethal fetal defect are associated with improved psychological outcome.

OBJECTIVE: The aim of the article is to examine the psychological impact, specifically symptoms of grief, post-traumatic stress and depression, in women and men who either terminated or continued a pregnancy following prenatal diagnosis of a lethal fetal defect. METHOD: This project investigated a diagnostically homogeneous group composed of 158 women and 109 men who lost a pregnancy to anencephaly, a lethal neural tube defect. Participants completed the Perinatal Grief Scale, Impact of Event Scale - Revised and Beck Depression Inventory-II, which measure symptoms of grief, post-traumatic stress and depression, respectively. Demographics, religiosity and pregnancy choices were also collected. Gender-specific analysis of variance was performed for instrument total scores and subscales. RESULTS: Women who terminated reported significantly more despair (p = 0.02), avoidance (p = 0.008) and depression (p = 0.04) than women who continued the pregnancy. Organizational religious activity was associated with a reduction in grief (Perinatal Grief Scale subscales) in both women (p = 0.02, p = 0.04 and p = 0.03) and men (p = 0.047). CONCLUSION: There appears to be a psychological benefit to women to continue the pregnancy following a lethal fetal diagnosis. Following a lethal fetal diagnosis, the risks and benefits, including psychological effects, of termination and continuation of pregnancy should be discussed in detail with an effort to be as nondirective as possible.
Authors
Cope, H; Garrett, ME; Gregory, S; Ashley-Koch, A
MLA Citation
Cope, Heidi, et al. “Pregnancy continuation and organizational religious activity following prenatal diagnosis of a lethal fetal defect are associated with improved psychological outcome..” Prenat Diagn, vol. 35, no. 8, Aug. 2015, pp. 761–68. Pubmed, doi:10.1002/pd.4603.
URI
https://scholars.duke.edu/individual/pub1102372
PMID
25872901
Source
pubmed
Published In
Prenat Diagn
Volume
35
Published Date
Start Page
761
End Page
768
DOI
10.1002/pd.4603

The epigenetics of Autism-Running beyond the bases

© 2014 by World Scientific Publishing Co. Pte. Ltd. All rights reserved. Previous studies have established that there is a strong genetic component to the development of ASD, but these genetic risks do not account for all of the heritability of the disorder. This raises the prospect that alternative, epigenetic mechanisms may play a role in ASD development. Epigenetic mechanisms facilitate temporal and spatial regulation of gene expression, but are independent of changes to the underlying DNA sequence. Because epigenetic profi les are labile, they represent an intriguing mechanism whereby environmental infl uences, which are not severe enough to alter the DNA sequence of a cell, may alter gene expression and cellular response and contribute to ASD. In this chapter, we discuss the role of DNA methylation and histone modifi cations in the development of ASD.
Authors
Gregory, SG
MLA Citation
Gregory, S. G. “The epigenetics of Autism-Running beyond the bases.” Frontiers in Autism Research: New Horizons for Diagnosis and Treatment, 2014, pp. 303–33. Scopus, doi:10.1142/9789814602167_0013.
URI
https://scholars.duke.edu/individual/pub1133004
Source
scopus
Published Date
Start Page
303
End Page
333
DOI
10.1142/9789814602167_0013

Integration of Whole Genome Methylation with Metabolomics Identifies Novel Cardiovascular Disease Genes

Authors
Shah, SH; Feng, S; Grass, E; Haynes, C; Chryst-Ladd, M; Craig, D; Hauser, ER; Newgard, CB; Kraus, WE; Gregory, SG
MLA Citation
Shah, Svati H., et al. “Integration of Whole Genome Methylation with Metabolomics Identifies Novel Cardiovascular Disease Genes.” Circulation, vol. 126, no. 21, LIPPINCOTT WILLIAMS & WILKINS, Nov. 2012.
URI
https://scholars.duke.edu/individual/pub1032417
Source
wos
Published In
Circulation
Volume
126
Published Date