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 (MS) and autism. 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 laboratory at Duke University is using cell signaling and immune cell flow sorting to establish the role of IL7R signaling in the development of MS; we are 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 of MS patients who do or do not respond to drug treatment.

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, and also Director of the Molecular Genomics Core at the DMPI in which we are applying a panoply of single cell approaches to basic and translation research.

Positions:

Professor in Neurology

Neurology, MS & Neuroimmunology
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:

Research Training In Neuro-Oncology

Administered By
Neurosurgery, Neuro-Oncology
Awarded By
National Institutes of Health
Role
Mentor
Start Date
End Date

Research Training In Neuro-Oncology

Administered By
Neurosurgery, Neuro-Oncology
Awarded By
National Institutes of Health
Role
Mentor
Start Date
End Date

Genetics Training Grant

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

Development of Circulating Molecular Predictors of Chemotherapy and Novel Hormonal Therapy Benefit in Men with Metastatic Castration Resistant Prostate Cancer (mCRPC)

Administered By
Medicine, Medical Oncology
Awarded By
Prostate Cancer Foundation
Role
Investigator
Start Date
End Date

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

Publications:

Single-Cell RNA Sequencing Reveals Cellular and Transcriptional Changes Associated With M1 Macrophage Polarization in Hidradenitis Suppurativa.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by recurrent abscesses, nodules, and sinus tracts in areas of high hair follicle and sweat gland density. These sinus tracts can present with purulent drainage and scar formation. Dysregulation of multiple immune pathways drives the complexity of HS pathogenesis and may account for the heterogeneity of treatment response in HS patients. Using transcriptomic approaches, including single-cell sequencing and protein analysis, we here characterize the innate inflammatory landscape of HS lesions. We identified a shared upregulation of genes involved in interferon (IFN) and antimicrobial defense signaling through transcriptomic overlap analysis of differentially expressed genes (DEGs) in datasets from HS skin, diabetic foot ulcers (DFUs), and the inflammatory stage of normal healing wounds. Overlap analysis between HS- and DFU-specific DEGs revealed an enrichment of gene signatures associated with monocyte/macrophage functions. Single-cell RNA sequencing further revealed monocytes/macrophages with polarization toward a pro-inflammatory M1-like phenotype and increased effector function, including antiviral immunity, phagocytosis, respiratory burst, and antibody-dependent cellular cytotoxicity. Specifically, we identified the STAT1/IFN-signaling axis and the associated IFN-stimulated genes as central players in monocyte/macrophage dysregulation. Our data indicate that monocytes/macrophages are a potential pivotal player in HS pathogenesis and their pathways may serve as therapeutic targets and biomarkers in HS treatment.
Authors
Mariottoni, P; Jiang, SW; Prestwood, CA; Jain, V; Suwanpradid, J; Whitley, MJ; Coates, M; Brown, DA; Erdmann, D; Corcoran, DL; Gregory, SG; Jaleel, T; Zhang, JY; Harris-Tryon, TA; MacLeod, AS
MLA Citation
Mariottoni, Paula, et al. “Single-Cell RNA Sequencing Reveals Cellular and Transcriptional Changes Associated With M1 Macrophage Polarization in Hidradenitis Suppurativa.Front Med (Lausanne), vol. 8, 2021, p. 665873. Pubmed, doi:10.3389/fmed.2021.665873.
URI
https://scholars.duke.edu/individual/pub1496054
PMID
34504848
Source
pubmed
Published In
Frontiers in Medicine
Volume
8
Published Date
Start Page
665873
DOI
10.3389/fmed.2021.665873

Characterization of a castrate-resistant prostate cancer xenograft derived from a patient of West African ancestry.

BACKGROUND: Prostate cancer is a clinically and molecularly heterogeneous disease, with highest incidence and mortality among men of African ancestry. To date, prostate cancer patient-derived xenograft (PCPDX) models to study this disease have been difficult to establish because of limited specimen availability and poor uptake rates in immunodeficient mice. Ancestrally diverse PCPDXs are even more rare, and only six PCPDXs from self-identified African American patients from one institution were recently made available. METHODS: In the present study, we established a PCPDX from prostate cancer tissue from a patient of estimated 90% West African ancestry with metastatic castration resistant disease, and characterized this model's pathology, karyotype, hotspot mutations, copy number, gene fusions, gene expression, growth rate in normal and castrated mice, therapeutic response, and experimental metastasis. RESULTS: This PCPDX has a mutation in TP53 and loss of PTEN and RB1. We have documented a 100% take rate in mice after thawing the PCPDX tumor from frozen stock. The PCPDX is castrate- and docetaxel-resistant and cisplatin-sensitive, and has gene expression patterns associated with such drug responses. After tail vein injection, the PCPDX tumor cells can colonize the lungs of mice. CONCLUSION: This PCPDX, along with others that are established and characterized, will be useful pre-clinically for studying the heterogeneity of prostate cancer biology and testing new therapeutics in models expected to be reflective of the clinical setting.
Authors
Patierno, BM; Foo, W-C; Allen, T; Somarelli, JA; Ware, KE; Gupta, S; Wise, S; Wise, JP; Qin, X; Zhang, D; Xu, L; Li, Y; Chen, X; Inman, BA; McCall, SJ; Huang, J; Kittles, RA; Owzar, K; Gregory, S; Armstrong, AJ; George, DJ; Patierno, SR; Hsu, DS; Freedman, JA
MLA Citation
Patierno, Brendon M., et al. “Characterization of a castrate-resistant prostate cancer xenograft derived from a patient of West African ancestry.Prostate Cancer Prostatic Dis, 2021. Pubmed, doi:10.1038/s41391-021-00460-y.
URI
https://scholars.duke.edu/individual/pub1466481
PMID
34645983
Source
pubmed
Published In
Prostate Cancer Prostatic Dis
Published Date
DOI
10.1038/s41391-021-00460-y

Circulating Tumor Cell Chromosomal Instability and Neuroendocrine Phenotype by Immunomorphology and Poor Outcomes in Men with mCRPC Treated with Abiraterone or Enzalutamide.

PURPOSE: While the detection of AR-V7 in circulating tumor cells (CTC) is associated with resistance to abiraterone or enzalutamide in men with metastatic castration-resistant prostate cancer (mCRPC), it only accounts for a minority of this resistance. Neuroendocrine (NE) differentiation or chromosomal instability (CIN) may be additional mechanisms that mediate resistance. EXPERIMENTAL DESIGN: PROPHECY was a multicenter prospective study of men with high-risk mCRPC starting abiraterone or enzalutamide. A secondary objective was to assess Epic CTC CIN and NE phenotypes before abiraterone or enzalutamide and at progression. The proportional hazards (PH) model was used to investigate the prognostic importance of CIN and NE in predicting progression-free survival and overall survival (OS) adjusting for CTC number (CellSearch), AR-V7, prior therapy, and clinical risk score. The PH model was utilized to validate this association of NE with OS in an external dataset of patients treated similarly at Memorial Sloan Kettering Cancer Center (MSKCC; New York, NY). RESULTS: We enrolled 118 men with mCRPC starting on abiraterone or enzalutamide; 107 were evaluable on the Epic platform. Of these, 36.4% and 8.4% were CIN positive and NE positive, respectively. CIN and NE were independently associated with worse OS [HR, 2.2; 95% confidence interval (CI), 1.2-4.0 and HR 3.8; 95% CI, 1.2-12.3, respectively] when treated with abiraterone/enzalutamide. The prognostic significance of NE positivity for worse OS was confirmed in the MSKCC dataset (n = 173; HR, 5.7; 95% CI, 2.6-12.7). CONCLUSIONS: A high CIN and NE CTC phenotype is independently associated with worse survival in men with mCRPC treated with abiraterone/enzalutamide, warranting further prospective controlled predictive studies to inform treatment decisions.
Authors
Brown, LC; Halabi, S; Schonhoft, JD; Yang, Q; Luo, J; Nanus, DM; Giannakakou, P; Szmulewitz, RZ; Danila, DC; Barnett, ES; Carbone, EA; Zhao, JL; Healy, P; Anand, M; Gill, A; Jendrisak, A; Berry, WR; Gupta, S; Gregory, SG; Wenstrup, R; Antonarakis, ES; George, DJ; Scher, HI; Armstrong, AJ
MLA Citation
Brown, Landon C., et al. “Circulating Tumor Cell Chromosomal Instability and Neuroendocrine Phenotype by Immunomorphology and Poor Outcomes in Men with mCRPC Treated with Abiraterone or Enzalutamide.Clin Cancer Res, vol. 27, no. 14, July 2021, pp. 4077–88. Pubmed, doi:10.1158/1078-0432.CCR-20-3471.
URI
https://scholars.duke.edu/individual/pub1478220
PMID
33820782
Source
pubmed
Published In
Clinical Cancer Research
Volume
27
Published Date
Start Page
4077
End Page
4088
DOI
10.1158/1078-0432.CCR-20-3471

Genetics of the chiari I and II malformations

Chiari malformations are considered to have a multifactorial etiology, likely influenced by environmental and genetic factors. This chapter will detail the evidence that supports a genetic contribution to the disorder, including discussions of twin studies, familial aggregation, co-occurrence with known genetic syndromes, and previous genetic studies. While no susceptibility genes have been identified to date, gene identification efforts are continuing. It is expected that researchers will have a more complete understanding of the specific genes and biological pathways that contribute to disease development in the coming years. The future benefits from genetic research of Chiari I and II may include the development of genetic tests that result in more accurate and faster diagnoses as well as new targeted treatment options for patients.
Authors
Markunas, CA; Ashley-Koch, AE; Gregory, SG
MLA Citation
Markunas, C. A., et al. “Genetics of the chiari I and II malformations.” The Chiari Malformations, 2020, pp. 289–97. Scopus, doi:10.1007/978-3-030-44862-2_23.
URI
https://scholars.duke.edu/individual/pub1459325
Source
scopus
Published Date
Start Page
289
End Page
297
DOI
10.1007/978-3-030-44862-2_23

Profiling serum neurofilament light chain and glial fibrillary acidic protein in primary progressive multiple sclerosis.

This study examined the utility of serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) as biomarkers in primary progressive multiple sclerosis in context with clinical severity, progression, and treatment. Using a single-molecule array (Quanterix), serum protein concentrations were measured from twenty-five participants semiannually for five years. There was no association between levels of either biomarker and disease severity, disease duration, or treatment group. Enrollment sNfL level was not associated with future clinical worsening. Precedent clinical worsening was not associated with last sGFAP measurement. These results suggest a limited role for these biomarkers in primary progressive disease management.
Authors
Giarraputo, J; Giamberardino, S; Arvai, S; Maichle, S; Eckstein, C; Newby, LK; Gregory, S
MLA Citation
Giarraputo, James, et al. “Profiling serum neurofilament light chain and glial fibrillary acidic protein in primary progressive multiple sclerosis.J Neuroimmunol, vol. 354, May 2021, p. 577541. Pubmed, doi:10.1016/j.jneuroim.2021.577541.
URI
https://scholars.duke.edu/individual/pub1476523
PMID
33725477
Source
pubmed
Published In
J Neuroimmunol
Volume
354
Published Date
Start Page
577541
DOI
10.1016/j.jneuroim.2021.577541