Dimitrios Davalos, Ph.D.
Assistant Professor, Molecular Medicine, CCLCM-CWRU
Lerner Research Institute,
9500 Euclid Avenue, Cleveland, Ohio 44195
Phone: (216) 444-7690
Fax: (216) 444-7927
We study the role that neuroimmune mechanisms play in brain function under physiological conditions and during neurological disease. Our main cells of interest are microglia, the resident immune cells of the central nervous system. Microglia are the first responders to any pathological insult—whether injury or disease— but their role in the physiological brain was greatly underappreciated for decades. Moreover, microglia have also historically been synonymous with inflammatory processes that can further damage neurons in the context of disease.
Using advanced microscopy technologies to follow the behavior of individual cells inside the intact living brain in real time, we previously showed—for the first time—that microglia continuously survey their environment and can rapidly contain small injuries within a few minutes without causing inflammatory damage. These findings inspired numerous studies aimed at understanding the mechanisms and the significance of such unexpectedly dynamic microglial functions for neuronal development, plasticity, function, and dysfunction.
Our recent studies have focused on microglial responses in the context of blood-brain barrier disruption, a pathological phenomenon that is very common among neurological diseases such as multiple sclerosis, Alzheimer’s disease, and stroke. We have also developed and published novel methods for imaging the living brain and spinal cord to follow ongoing biological processes over time. Our research combines cutting-edge imaging techniques with molecular, cellular and genetic approaches to study the interactions between blood vessels, neurons, and glia, and to better understand how their structural and functional relationships change between health and disease. By studying these relationships in real time, our ultimate goal is to expand our understanding of the role of microglia in brain function, and to identify new targets for therapeutic intervention for neurological diseases.
1. Davalos D, Mahajan KR, Trapp BD. (2019) Brain fibrinogen deposition plays a key role in MS pathophysiology - Yes. Mult Scler. Jul 18:1352458519852723.PMID: 31315512
2. Merlini M, Rafalski VA, Rios Coronado PE, Gill TM, Ellisman M, Muthukumar G, Subramanian KS, Ryu JK, Syme CA, Davalos D, Seeley WW, Mucke L, Nelson RB, Akassoglou K. (2019) Fibrinogen Induces Microglia-Mediated Spine Elimination and Cognitive Impairment in an Alzheimer's Disease Model. Neuron pii: S0896-6273(19)30015-7. PMID: 30737131; PMCID:PMC6602536
3. Ryu JK, Rafalski VA, Meyer-Franke A, Adams RA, Poda SB, Rios Coronado PE, Pedersen LØ, Menon V, Baeten KM, Sikorski SL, Bedard C, Hanspers K, Bardehle S, Mendiola AS, Davalos D, Machado MR, Chan JP, Plastira I, Petersen MA, Pfaff SJ, Ang KK, Hallenbeck KK, Syme C, Hakozaki H, Ellisman MH, Swanson RA, Zamvil SS, Arkin MR, Zorn SH, Pico AR, Mucke L, Freedman SB, Stavenhagen JB, Nelson RB, Akassoglou K. (2018) Fibrin-targeting immunotherapy protects against neuroinflammation and neurodegeneration. Nat Immunol. 19(11):1212-1223. PMID: 30323343; PMCID: PMC6317891
4. Sayed FA, Telpoukhovskaia M, Kodama L, Li Y, Zhou Y, Le D, Hauduc A, Ludwig C, Gao F, Clelland C, Zhan L, Cooper YA, Davalos D, Akassoglou K, Coppola G, Gan L. (2018) Differential effects of partial and complete loss of TREM2 on microglial injury response and tauopathy. Proc Natl Acad Sci USA 115(40):10172-10177. PMID: 30232263; PMCID: PMC6176614
5. Krabbe G, Minami SS, Etchegaray JI, Taneja P, Djukic B, Davalos D, Le D, Lo I, Zhan L, Reichert MC, Sayed F, Merlini M, Ward ME, Perry DC, Lee SE, Sias A, Parkhurst CN, Gan WB, Akassoglou K, Miller BL, Farese RV Jr, Gan L. (2017) Microglial NFκB-TNFα hyperactivation induces obsessive-compulsive behavior in mouse models of progranulin-deficient frontotemporal dementia. Proc Natl Acad Sci USA 114(19):5029-5034. doi: 10.1073/pnas.1700477114. PMID: 28438992; PMCID: PMC5441749
6. Tsai HH, Niu J, Munji R, Davalos D, Chang J, Zhang H, Tien AC, Kuo CJ, Chan JR, Daneman R, Fancy SP. (2016) Oligodendrocyte precursors migrate along vasculature in the developing nervous system. Science 351(6271):379-84. PMID: 26798014; PMCID: PMC5472053
7. Akassoglou K, Agalliu D, Chang CJ, Davalos D, Grutzendler J, Hillman EM, Khakh BS, Kleinfeld D, McGavern DB, Nelson SJ, Zlokovic BV. (2016) Neurovascular and Immuno-Imaging: From Mechanisms to Therapies. Proceedings of the Inaugural Symposium. Front Neurosci 10:46. PMID: 26941593; PMCID: PMC4761864
8. Baeza-Raja B, Sachs BD, Li P, Christian F, Vagena E, Davalos D, Le Moan N, Ryu JK, Sikorski SL, Chan JP, Scadeng M, Taylor SS, Houslay MD, Baillie GS, Saltiel AR, Olefsky JM, Akassoglou K. (2016) p75 Neurotrophin Receptor Regulates Energy Balance in Obesity. Cell Rep 14(2):255-68. PMID: 26748707; PMCID: PMC4831919
9. Le Moan N, Baeten KM, Rafalski VA, Ryu JK, Rios Coronado PE, Bedard C, Syme C, Davalos D, Akassoglou K. (2015) Hypoxia Inducible Factor-1α in Astrocytes and/or Myeloid Cells Is Not Required for the Development of Autoimmune Demyelinating Disease. eNeuro 2(2). PMID: 26213713; PMCID: PMC4511492
10. Gyoneva S, Davalos D, Biswas D, Swanger SA, Garnier-Amblard E, Loth F, Akassoglou K, Traynelis SF. (2014) Systemic inflammation regulates microglial responses to tissue damage in vivo. Glia 62(8):1345-60. PMID: 24807189; PMCID: PMC4408916
11. Davalos D, Baeten KM, Whitney MA, Mullins ES, Friedman B, Olson ES, Ryu JK, Smirnoff DS, Petersen MA, Bedard C, Degen JL, Tsien RY, Akassoglou K. (2014) Early detection of thrombin activity in neuroinflammatory disease. Ann Neurol 75(2):303-8. PMID: 24740641; PMCID: PMC4049631
12. Chen W, Guo Y, Walker EJ, Shen F, Jun K, Oh SP, Degos V, Lawton MT, Tihan T, Davalos D, Akassoglou K, Nelson J, Pile-Spellman J, Su H, Young WL. (2013) Reduced mural cell coverage and impaired vessel integrity after angiogenic stimulation in the Alk1-deficient brain. Arterioscler Thromb Vasc Biol 33(2):305-10. PMID: 23241407; PMCID: PMC3569037
13. Merlini M, Davalos D, Akassoglou K. (2012) In vivo imaging of the neurovascular unit in CNS disease. Intravital 1(2):87-94. PMID: 25197615; PMCID: PMC4155511
14. Davalos D, Ryu JK, Merlini M, Baeten KM, Le Moan N, Petersen MA, Deerinck TJ, Smirnoff DS, Bedard C, Hakozaki H, Gonias Murray S, Ling JB, Lassmann H, Degen JL, Ellisman MH, Akassoglou K. (2012) Fibrinogen-induced perivascular microglial clustering is required for the development of axonal damage in neuroinflammation. Nat Commun 3:1227. PMID: 23187627; PMCID: PMC3514498
15. Kwan W, Träger U, Davalos D, Chou A, Bouchard J, Andre R, Miller A, Weiss A, Giorgini F, Cheah C, Möller T, Stella N, Akassoglou K, Tabrizi SJ, Muchowski PJ. (2012) Mutant huntingtin impairs immune cell migration in Huntington disease. J Clin Invest 122(12):4737-47. PMID: 23160193; PMCID: PMC3533551
16. Baeza-Raja B, Li P, Le Moan N, Sachs BD, Schachtrup C, Davalos D, Vagena E, Bridges D, Kim C, Saltiel AR, Olefsky JM, Akassoglou K. (2012) p75 neurotrophin receptor regulates glucose homeostasis and insulin sensitivity. Proc Natl Acad Sci U S A 109(15):5838-43. PMID: 22460790; PMCID: PMC3326459
17. Davalos D, Akassoglou K. (2012) In vivo imaging of the mouse spinal cord using two-photon microscopy. J Vis Exp Jan 5;(59):e2760. PMID: 22258623; PMCID: PMC3369767
18. Davalos D, Akassoglou K. (2012) Fibrinogen as a key regulator of inflammation in disease. Semin Immunopathol 34(1):43-62. PMID: 22037947
19. Drew PJ, Shih AY, Driscoll JD, Knutsen PM, Blinder P, Davalos D, Akassoglou K, Tsai PS, Kleinfeld D. (2010) Chronic optical access through a polished and reinforced thinned skull. Nat Methods 7(12):981-4. PMID: 20966916; PMCID: PMC3204312
20. Ryu JK, Davalos D, Akassoglou K. (2009) Fibrinogen signal transduction in the nervous system. J Thromb Haemost 7 Suppl 1:151-4. PMID: 19630789; PMCID: PMC2888044
21. Davalos D, Lee JK, Smith WB, Brinkman B, Ellisman MH, Zheng B, Akassoglou K. (2008) Stable in vivo imaging of densely populated glia, axons and blood vessels in the mouse spinal cord using two-photon microscopy. J Neurosci Methods 169(1):1-7. PMID: 18192022; PMCID: PMC2647134
22. Adams RA, Schachtrup C, Davalos D, Tsigelny I, Akassoglou K. (2007) Fibrinogen signal transduction as a mediator and therapeutic target in inflammation: lessons from multiple sclerosis. Curr Med Chem 14(27):2925-36. PMID: 18045138
23. Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, Littman DR, Dustin ML, Gan WB. (2005) ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 8(6):752-8. PMID: 15895084
Neurological disability in multiple sclerosis (MS) is caused by an inflammatory response in the central nervous system (CNS) that damages axons and myelin. These inflammation “hotspots” occur around leaky blood vessels and are an early indicator of disease. Under normal conditions, healthy blood vessels provide a physical border between the brain and circulating blood, called the blood-brain barrier (BBB). However, this barrier becomes compromised very early in the course of MS, allowing pro-inflammatory cells from the blood to infiltrate the CNS and initiate a cascade of neurological damage. It is not known what mechanisms cause the BBB disruption.
A new internally funded award, called the Co-Laboratories Award, encourages new, "start-up" collaborations that bring together researchers from different laboratories to investigate and attack disease from many angles, drawing on the unique expertise and innovations that each laboratory has to offer. The award provides up to $100,000 in project funding per year for up to two years. In its inaugural year, the award funded two exciting cross-disciplinary projects that will investigate neuronal dysfunction in alcohol abuse and smooth muscle hyperplasia in Crohn's disease.