Rheumatology, Immunology and Allergy
- Rheumatology Fellowship, University of California, San Francisco, CA | 2001-2004
- Chief Resident, University of California, San Francisco, CA | 2000-2001
- Internal Medicine Residency, University of California, San Francisco, CA | 1997-2000
- M.D. (MSTP Program) Baylor College of Medicine, Houston, TX | 1988-1997
- Post-doctoral fellowship, Biochemistry, Baylor College of Medicine | 1994-1995
- Ph.D., Cell Biology, Baylor College of Medicine, Houston, TX | 1989-1994
- B.A. Biology, magna cum laude, Austin College, Sherman, TX | 1984-1987
- Associate Dean of Research, 2019-present, University of Oklahoma Health Sciences Center, Oklahoma City, OK
- Professor of Medicine with tenure, 2015-present, University of Oklahoma Health Sciences Center, Oklahoma City, OK
- The James R. McEldowney Chair in Immunology, 2009-present University of Oklahoma Health Sciences Center, Oklahoma City, OK
- Adjunct Professor of Cell Biology, 2015-present, University of Oklahoma Health Sciences Center, Oklahoma City, OK
- Adjunct Professor of Microbiology and Immunology, 2015-present, University of Oklahoma Health Sciences Center, Oklahoma City, OK
- Associate Professor of Medicine with tenure, 2012-2015, University of Oklahoma Health Sciences Center, Oklahoma City, OK
- Assistant Professor of Medicine with tenure track, 2009-2012, University of Oklahoma Health Sciences Center, Oklahoma City, OK
- Adjunct Assistant Professor of Microbiology and Immunology, 2006-2012, University of Oklahoma Health Sciences Center, Oklahoma City, OK
- Assistant Professor of Medicine, tenure track, 2004-2006, University of California, San Francisco, CA
- Adjunct Assistant Professor of Medicine, 2003-2004, University of California, San Francisco, CA
The overarching interest of the Humphrey lab is to understanding the role of myeloid cells in human diseases including osteoporosis, osteoarthritis, heart failure with preserved ejection fraction, and Alzheimer’s disease.
Full list of publications: https://www.ncbi.nlm.nih.gov/sites/myncbi/mary.humphrey.1/bibliography/40317085/public/?sort=date&direction=ascending
- ITAM regulation of osteoclastogenesis and bone remodeling. Bone is a dynamic tissue undergoing a constant remodeling process through out life. During remodeling, osteoclasts resorb bone and osteoblasts form new bone. Abnormal bone remodeling, secondary to increased osteoclast maturation or activation, contributes to bone destruction in inflammatory arthritis and osteoporosis. RANK Ligand, a TNF family member produced by both T cells and osteoblasts, is a differentiation and activation signal for osteoclasts. Discerning other immunomodulatory signals that govern osteoclast development, function, or survival is essential to understanding both normal as well as pathological bone processes. Towards this end our research focuses on the molecular mechanisms that lead to osteoclast differentiation and activation. My early work as a post-doctoral fellow and junior faculty at UCSF focused on the novel role of immunoreceptor tyrosine based activation motif (ITAM) containing adapter proteins in osteoclast differentiation and bone remodeling. We focused on the ITAM adapter proteins DAP12 and FcRγ and were the first to show that these adapter proteins are critical for homeostatic bone remodeling but dispensable for estrogen-deficient induced bone loss. Additional mechanistic studies provided further understanding of the role of DAP12 and its associated immunoreceptor, TREM2, in osteoclastogenesis. We also identified the first Immunoreceptor tyrosine-based inhibitory motif (ITIM) containing immunoreceptor, CLM-1, that negatively regulates osteoclastogenesis. The significance of this work was recognized and I received a Presidential Early Career Award in Science and Engineering in 2010.
- Humphrey, M. B.*, A. Mócsai*, J.A.G. Van Ziffle, Y. Hu, A. Burghardt, S. Spusta, S. Majumdar, L. L. Lanier, C. A. Lowell, M. C. Nakamura. The Immunomodulatory Adapter Proteins DAP12 and FcR Regulate Development of Functional Osteoclasts through the Syk Tyrosine Kinase. Proceedings of the National Academy of Sciences. 2004, 101:6158-6163. (* Co-first authors) PMCID:PMC395939
- Humphrey, M.B., K. Ogasawara, W. Yao, S. C. Spusta, M. R. Daws, N. E. Lane, L. L. Lanier, M. C. Nakamura. The Signaling Adapter Protein DAP12 Regulates Multinucleation During Osteoclast Development. Journal of Bone and Mineral Research.2004, 19:224-234.
- Humphrey, M.B., M. R. Daws, S. C. Spusta, E. C. Niemi, J. A. Torchia, L. L. Lanier, W. E. Seaman, and M. C. Nakamura. TREM2, a DAP12-associated Receptor, Regulates Osteoclast Differentiation and Function. Journal of Bone and Mineral Research, 2006, 21:237-245.
- Wu, Y., J.A. Torchia, W. Yao, N.E. Lane, L.L. Lanier, M.C.Nakamura, and M.B. Humphrey**.Bone Microenvironment Specific Roles of ITAM Signaling in Bone Remodeling Induced by Acute Estrogen-deficiency.Public Library of Science ONE, 2007, 2(7):E586. doi:10371/ journal.pone 0000586. PMCID:PMC1895921
- Identifying novel regulators of osteoclastogenesis. I have continued investigating the regulation of ITAM signaling and the signaling cross-talk between DAP12 with Toll-like receptors. This work has uncovered several novel findings concerning lipid phosphatases and signaling adapter proteins that bind to and facilitate inhibitory signaling from DAP12 in response to TREM2 and TLR4 engagement.
- Peng, Q., Coggeshall, K.M., Torchia, J.A., and M.B. Humphrey**. TREM2- and DAP12-Dependent Activation of PI3K Requires DAP10 and is Inhibited by SHIP1. Science Signaling, 2010, 3 (122):ra38. PMID:20484116PMCID: PMC2900152
- Peng Q, O'Loughlin JL, Humphrey MB. DOK3 negatively regulates LPS responses and endotoxin tolerance. PLoS One. 2012;7(6):e39967. doi: 10.1371/journal.pone.0039967. Epub 2012 Jun 27. PubMed PMID: 22761938 PMCID: PMC3384629
- Peng Q, Long CL, Malhotra S, and MB Humphrey. A physical interaction between the adaptor proteins DOK3 and DAP12 is required to inhibit lipopolysaccharide signaling in macrophages. Science Signaling. August 2013; 6(289):ra72doi:10.1126/scisignal.2003801 PMCID: PMC3923308
- Cai X, Xing J, Long CL, Peng Q, Humphrey MB. DOK3 Modulates Bone Remodeling by Negatively Regulating Osteoclastogenesis and Positively Regulating Osteoblastogenesis. J Bone Miner Res. 2017 Jun doi: 10.1002/jbmr.3205.
- Identifying novel regulators of bone cell development: In collaboration with others, we have continued to identify novel regulators of bone cells including osteoblasts and osteoclasts. We were the first to identify a role of CD73 in osteoblastogenesis and function. We were also the first to determine the role of E proteins in osteoclastogenesis in vitro and in vivo. Through collaborations with Dr. Leo Tsiokas (OUHSC), we have identified novel roles for TRPC1 and I-mfa in osteoclastogenesis. Ongoing studies include the role TRPC1 in the regulation of parathyroid hormone secretion and calcium sensing receptor signaling in the parathyroid gland, osteoblasts, and osteocytes. Additionally, we are investigating the role of i-mfa (Midi1) in hematopoietic stem cell renewal and myelopoiesis.
- Takedachi M, Oohara H, Smith BJ, Iyama M, Kobashi M, Maeda K, Long CL, Humphrey MB, Stoecker BJ, Toyosawa S, Thompson LF, and S Murakami. CD73-generated adesonine promotes osteoblast differentiation. Journal of Cellular Physiology. 2011 doi: 10.1002/jcp.23001.
- Long CL, Berry WL, Zhao Y, Sun XH, and MB Humphrey. E proteins regulate osteoclast maturation and survival. Journal of Bone and Mineral Research. 2012, Jul 13, doi 10.1002/jbmr.1707 PMID: 22807064 PMCID: PMC3495082
- Ong EC, Nesin V, Long CL, Bai CX, Guz JL, Ivanov IP, Abramowitz J, Birnbaumer L, Humphrey MB, Tsiokas L. A TRPC1-dependent pathway regulates osteoclast formation and function. Journal of Biological Chemistry. 2013 Aug 2;288(31):22219-32. doi: 10.1074/jbc.M113.459826.
- Identifying mechanisms of osteoarthritis. More recently, I have collaborated with Dr. WilliamSonntag (OUHSC) on the role of IGF-1 in bone during the lifespan of mice including old age. His expertise in aging coupled with my expertise in bone models of osteoarthritis and high fat diet-induced obesity, have provided for a highly successfully team approach to understanding how aging impacts bone health. Additional studies with Dr. Matlock Jeffries (OUHSC) have uncovered epigenetic changes in articular cartilage and the underling subchondral bone that correlate with osteoarthritis.
- Jeffries MA, Donica M, Maker L, Stevenson M, Annan AC, Humphrey MB**, James JA, and AH Sawalha.Genome-wide DNA Methylation study identifies significant epigenomic changes in osteoarthritic cartilage. Arthritis and Rheumatology. 2014; June; 66(10):2804-15.
- Jeffries, MA, James JA, Humphrey MB,AH Sawalha. Genome-wide DNA methylation study identifies significant epigenomic changes in osteoarthritic subchondral bone and similarity to overlying cartilage.Arthritis and Rheumatology. 2016; June; 68(6):1403-1414. Epub
- Ashpole NM, Herron JC, Mitschelen MC, Farley JA, Logan S, yan H, Ungvari Z, Hodges EL, Csiszar A, Ikeno Y, Humphrey MB, and WE Sonntag. IGF-1 regulates vertebral bone aging through sex-specific and time-dependent mechanisms. Journal of Bone and Mineral Research. 2016; Feb, 31(2):443-54. Epub 2015 Sept. 3
- Ashpole NM, Herron JC, Estep PN, Logan S, Hodges EL, Yabluchansky A, Humphrey MB, Sonntag WE. Differential effects of IGF-1 deficiency during the life span on structural and biomechanical properties in the tibia of aged mice. Age. 2016, 38(2):38;doi: 10.1007/s11357-016-9902-5. Epub 2016 Mar 11 (IF 3.39)
- Vagal nerve modulation of atrial fibrillation and heart failure with preserved ejection fraction (diastolic heart failure). An exciting new area of investigation includes an intriguing collaboration with Dr. Stavros Stavrakis (OUHSC) determining the effects of vagal nerve stimulation on atrial fibrillation. In humans, we have found that brief vagal nerve stimulation via the tragus branch (in the ear) of the vagal nerve, reduces atrial fibrillation and systemic inflammation associated with atrial fibrillation. As these studies in humans show that vagal nerve stimulation impacts atrial fibrillation, I am very excited about our continued collaboration testing the influence of vagal nerve stimulation on heart failure with preserved ejection fraction in a rat model. Early studies show protection from cardiac fibrosis and reduction in HFpEF in this rat model. We are now focusing on mechanistic studies to determine the role of immune cells in this model and response to vagal nerve stimulation.
- Zhou L, Filiberti A, Humphrey MB, Fleming CD, Scherlag BJ, Po SS, Stavrakis S. Low-level transcutaneous vagus nerve stimulation attenuates cardiac remodeling in a rat model of heart failure with preserved ejection fraction. Exp Physiol. 2019 Jan;104(1):28-38. doi: 10.1113/EP087351.
- Stavrakis S, Humphrey MB, Scherlag B, Iftikhar O, Parwani P, Abbas M, Filiberti A, Fleming C, Hu Y, Garabelli P, McUnu A, Peyton M, Po SS. Low-level transcutaneous vagus nerve stimulation suppresses Post-Operative Atrial Fibrillation and Inflammation: A Randomized Study. JACC Clin Electrophysiol. 2017 Sep;3(9):929-938. doi: 10.1016/j.jacep.2017.02.019.
- Stavrakis S, Humphrey MB, Scherlag BJ, Hu Y, Jackman WM, Nakagawa H, Lockwood D, Lazzara R, Po SS. Low level transcutaneous electrical vagus nerve stimulation suppresses atrial fibrillation. J Am Coll Cardiol. March 2015; 65(9): 867-75. doi: 10.1016/j.jacc.2014.12.026
- Stavrakis S, Humphrey MB, Po SS.Vagal modulation of atrial fibrillation. J Am Coll Cardiol 2015; 66:978. PMID: 26293771
Techniques that trainees might gain experience with in our lab includes Western Blotting, Immunoprecipitation, Cell culture, Elisa, Molecular Biology, Protein Expression, Fusion Protein production, Flow cytometry, Micro array, Immunofluorescent microscopy, Animal experiments, Osteoclast migration and resorption assays, Micro Computed tomography (microCT) of mouse bones, bone histology, and bone histomorphometry.