Simon Gregory

Overview:

My research involves elucidating the molecular mechanisms underlying complex neurological diseases, such as multiple sclerosis (MS), autism, Alzheimer's disease (AD), and brain tumors. We use a variety of (epi)genetic, genomic, transcriptomic, and leading edge technologies to identify the underpinnings of disease development and progression. 

With respect to autism, we are investigating the use of oxytocin to improve social reciprocity in children with the disorder and developing (epi)genetic and transcriptomic predictors of plasma levels of oxytocin. We are also unraveling the mechanisms associated with sociability in animal models of autism.

In the fields of AD and brain tumor research, my lab is using or developing leading edge single cell and spatial expression profiling platforms to unravel the molecular mechanisms of pathology or tissue related microenvironmental changes associated with disease development and progression.

My MS laboratory at Duke University is exploring the use of high sensitivity assays to develop a trajectory of disease development in progressive MS; we are exploring the use of endogenous oxysterols to trigger remyelination of white matter injury in MS; and establishing the immune expression and receptor profile in stable or progressive MS patients. 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 Director of the Duke Center for Research in Autoimmunity and MS within the Duke Department of Neurology.

Positions:

Professor in Neurology

Neurology, MS & Neuroimmunology
School of Medicine

Vice Chair for Research in the Department of Neurology

Neurology
School of Medicine

Research Professor in Molecular Genetics and Microbiology

Molecular Genetics and Microbiology
School of Medicine

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 (United Kingdom)

Grants:

High-Resolution CGH Characterization of Brain Tumors

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

Linkage and candidate gene analysis in non-syndromic Chiari type I

Administered By
Duke Molecular Physiology Institute
Awarded By
National Institutes of Health
Role
Co-Principal Investigator
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

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

Specific and Pervasive Symptoms in Adults with Multiple Sclerosis Using the MURDOCK-MS Dataset: A Secondary Analysis

Administered By
School of Nursing
Awarded By
National Institutes of Health
Role
Significant Contributor
Start Date
End Date

Publications:

Adolescent peer struggles predict accelerated epigenetic aging in midlife.

This study examined struggles to establish autonomy and relatedness with peers in adolescence and early adulthood as predictors of advanced epigenetic aging assessed at age 30. Participants (N = 154; 67 male and 87 female) were observed repeatedly, along with close friends and romantic partners, from ages 13 through 29. Observed difficulty establishing close friendships characterized by mutual autonomy and relatedness from ages 13 to 18, an interview-assessed attachment state of mind lacking autonomy and valuing of attachment at 24, and self-reported difficulties in social integration across adolescence and adulthood were all linked to greater epigenetic age at 30, after accounting for chronological age, gender, race, and income. Analyses assessing the unique and combined effects of these factors, along with lifetime history of cigarette smoking, indicated that each of these factors, except for adult social integration, contributed uniquely to explaining epigenetic age acceleration. Results are interpreted as evidence that the adolescent preoccupation with peer relationships may be highly functional given the relevance of such relationships to long-term physical outcomes.
Authors
Allen, JP; Danoff, JS; Costello, MA; Loeb, EL; Davis, AA; Hunt, GL; Gregory, SG; Giamberardino, SN; Connelly, JJ
MLA Citation
Allen, Joseph P., et al. “Adolescent peer struggles predict accelerated epigenetic aging in midlife.Dev Psychopathol, Apr. 2022, pp. 1–14. Pubmed, doi:10.1017/S0954579422000153.
URI
https://scholars.duke.edu/individual/pub1515891
PMID
35379374
Source
pubmed
Published In
Dev Psychopathol
Published Date
Start Page
1
End Page
14
DOI
10.1017/S0954579422000153

Lifetime marijuana use and epigenetic age acceleration: A 17-year prospective examination.

AIMS: This study was designed to assess links between lifetime levels of marijuana use and accelerated epigenetic aging. DESIGN: Prospective longitudinal study, following participants annually from age 13 to age 30. SETTING AND PARTICIPANTS: A community sample of 154 participants recruited from a small city in the Southeastern United States. MEASUREMENTS: Participants completed annual assessments of marijuana use from age 13 to age 29 and provided blood samples that yielded two indices of epigenetic aging (DNAmGrimAge and DunedinPoAm) at age 30. Additional covariates examined included history of cigarette smoking, anxiety and depressive symptoms, childhood illness, gender, adolescent-era family income, and racial/ethnic minority status. FINDINGS: Lifetime marijuana use predicted accelerated epigenetic aging, with effects remaining even after covarying cell counts, demographic factors and chronological age (β's = 0.32 & 0.27, p's < 0.001, 95% CI's = 0.21-0.43 & 0.16-0.39 for DNAmGrimAge and DunedinPoAm, respectively). Predictions remained after accounting for cigarette smoking (β's = 0.25 & 0.21, respectively, p's < 0.001, 95% CI's = 0.14-0.37 & 0.09-0.32 for DNAmGrimAge and DunedinPoAm, respectively). A dose-response effect was observed and there was also evidence that effects were dependent upon recency of use. Effects of marijuana use appeared to be fully mediated by hypomethylation of a site linked to effects of hydrocarbon inhalation (cg05575921). CONCLUSIONS: Marijuana use predicted epigenetic changes linked to accelerated aging, with evidence suggesting that effects may be primarily due to hydrocarbon inhalation among marijuana smokers. Further research is warranted to explore mechanisms underlying this linkage.
Authors
Allen, JP; Danoff, JS; Costello, MA; Hunt, GL; Hellwig, AF; Krol, KM; Gregory, SG; Giamberardino, SN; Sugden, K; Connelly, JJ
MLA Citation
Allen, Joseph P., et al. “Lifetime marijuana use and epigenetic age acceleration: A 17-year prospective examination.Drug Alcohol Depend, vol. 233, Apr. 2022, p. 109363. Pubmed, doi:10.1016/j.drugalcdep.2022.109363.
URI
https://scholars.duke.edu/individual/pub1512037
PMID
35231715
Source
pubmed
Published In
Drug Alcohol Depend
Volume
233
Published Date
Start Page
109363
DOI
10.1016/j.drugalcdep.2022.109363

Human distal lung maps and lineage hierarchies reveal a bipotent progenitor.

Mapping the spatial distribution and molecular identity of constituent cells is essential for understanding tissue dynamics in health and disease. We lack a comprehensive map of human distal airways, including the terminal and respiratory bronchioles (TRBs), which are implicated in respiratory diseases1-4. Here, using spatial transcriptomics and single-cell profiling of microdissected distal airways, we identify molecularly distinct TRB cell types that have not-to our knowledge-been previously characterized. These include airway-associated LGR5+ fibroblasts and TRB-specific alveolar type-0 (AT0) cells and TRB secretory cells (TRB-SCs). Connectome maps and organoid-based co-cultures reveal that LGR5+ fibroblasts form a signalling hub in the airway niche. AT0 cells and TRB-SCs are conserved in primates and emerge dynamically during human lung development. Using a non-human primate model of lung injury, together with human organoids and tissue specimens, we show that alveolar type-2 cells in regenerating lungs transiently acquire an AT0 state from which they can differentiate into either alveolar type-1 cells or TRB-SCs. This differentiation programme is distinct from that identified in the mouse lung5-7. Our study also reveals mechanisms that drive the differentiation of the bipotent AT0 cell state into normal or pathological states. In sum, our findings revise human lung cell maps and lineage trajectories, and implicate an epithelial transitional state in primate lung regeneration and disease.
Authors
Kadur Lakshminarasimha Murthy, P; Sontake, V; Tata, A; Kobayashi, Y; Macadlo, L; Okuda, K; Conchola, AS; Nakano, S; Gregory, S; Miller, LA; Spence, JR; Engelhardt, JF; Boucher, RC; Rock, JR; Randell, SH; Tata, PR
MLA Citation
Kadur Lakshminarasimha Murthy, Preetish, et al. “Human distal lung maps and lineage hierarchies reveal a bipotent progenitor.Nature, vol. 604, no. 7904, Apr. 2022, pp. 111–19. Pubmed, doi:10.1038/s41586-022-04541-3.
URI
https://scholars.duke.edu/individual/pub1515768
PMID
35355018
Source
pubmed
Published In
Nature
Volume
604
Published Date
Start Page
111
End Page
119
DOI
10.1038/s41586-022-04541-3

Single Cell RNA-Seq Analysis of Human Red Cells.

Human red blood cells (RBCs), or erythrocytes, are the most abundant blood cells responsible for gas exchange. RBC diseases affect hundreds of millions of people and impose enormous financial and personal burdens. One well-recognized, but poorly understood feature of RBC populations within the same individual are their phenotypic heterogeneity. The granular characterization of phenotypic RBC variation in normative and disease states may allow us to identify the genetic determinants of red cell diseases and reveal novel therapeutic approaches for their treatment. Previously, we discovered diverse RNA transcripts in RBCs that has allowed us to dissect the phenotypic heterogeneity and malaria resistance of sickle red cells. However, these analyses failed to capture the heterogeneity found in RBC sub-populations. To overcome this limitation, we have performed single cell RNA-Seq to analyze the transcriptional heterogeneity of RBCs from three adult healthy donors which have been stored in the blood bank conditions and assayed at day 1 and day 15. The expression pattern clearly separated RBCs into seven distinct clusters that include one RBC cluster that expresses HBG2 and a small population of RBCs that express fetal hemoglobin (HbF) that we annotated as F cells. Almost all HBG2-expessing cells also express HBB, suggesting bi-allelic expression in single RBC from the HBG2/HBB loci, and we annotated another cluster as reticulocytes based on canonical gene expression. Additional RBC clusters were also annotated based on the enriched expression of NIX, ACVR2B and HEMGN, previously shown to be involved in erythropoiesis. Finally, we found the storage of RBC was associated with an increase in the ACVR2B and F-cell clusters. Collectively, these data indicate the power of single RBC RNA-Seq to capture and discover known and unexpected heterogeneity of RBC population.
Authors
Jain, V; Yang, W-H; Wu, J; Roback, JD; Gregory, SG; Chi, J-T
MLA Citation
Jain, Vaibhav, et al. “Single Cell RNA-Seq Analysis of Human Red Cells.Front Physiol, vol. 13, 2022, p. 828700. Pubmed, doi:10.3389/fphys.2022.828700.
URI
https://scholars.duke.edu/individual/pub1518969
PMID
35514346
Source
pubmed
Published In
Frontiers in Physiology
Volume
13
Published Date
Start Page
828700
DOI
10.3389/fphys.2022.828700

Correction: Single-cell RNA-seq reveals transcriptomic heterogeneity mediated by host-pathogen dynamics in lymphoblastoid cell lines.

Authors
SoRelle, ED; Dai, J; Bonglack, EN; Heckenberg, EM; Zhou, JY; Giamberardino, SN; Bailey, JA; Gregory, SG; Chan, C; Luftig, MA
MLA Citation
SoRelle, Elliott D., et al. “Correction: Single-cell RNA-seq reveals transcriptomic heterogeneity mediated by host-pathogen dynamics in lymphoblastoid cell lines.Elife, vol. 10, Nov. 2021. Pubmed, doi:10.7554/eLife.75422.
URI
https://scholars.duke.edu/individual/pub1501343
PMID
34762045
Source
pubmed
Published In
Elife
Volume
10
Published Date
DOI
10.7554/eLife.75422