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My overarching hypothesis is that the immune system – driven by an autoreactivity to CNS-derived antigens – plays a fundamental role in neuronal plasticity within the CNS. B cells, T cells, and natural killer (NK) T cells comprise the adaptive component of the immune system, with their interactions initiated by antigen recognition. In stroke, I hypothesize that long-term plasticity requires autoreactive T and B cell responses within the parenchyma, derived from lymphocyte populations sensitized to CNS antigens in the periphery. My preliminary data show that CD4 and CD8 T cells, as well as B cells, respond to specific immunogenic peptide sequences from neuronally-derived proteins that could potentially facilitate such processes as dendritic pruning, synaptogenesis, and axonal outgrowth in the ischemic brain. Although I use preclinical studies to investigate the mechanisms by which autoimmune responses affect post-stroke plasticity (e.g., protection from excitotoxicity, dendritic pruning), it is critical to concomitantly confirm and characterize these cells in humans. My clinical studies into the role of neuroinflammation during brain injury and repair has expanded beyond the field of ischemic stroke to also include subjects with amnestic mild cognitive impairment and pediatric patients on ventilator and hemodynamic support who experience stroke. The combination of preclinical and clinical studies reflects both my own training, which included a clinical postdoctoral fellowship, and my ongoing scientific philosophy that translational research will hasten the collective understanding of functional recovery during and following brain injury.
Project Title: Rethinking repair: long-term adaptive immunity supports functional recovery for stroke patients
Project Number: 19EIA34760279
Source of Funding: American Heart Association
Duration of Project: 04/2019-03/2024
Project Title: B cells alter adaptive autoimmunity to protect from ischemic injury after stroke
Project Number: R01 NS088555
Duration of Project: 02/2015-01/2020
Project Title: Protective mechanisms of B cell autoreactive for the NMDA receptor: saving synapses following stroke
Source of Funding: The Dana Foundation, The David Mahoney Neuroimaging Program
Duration of Project: 09/2016-09/2020 (no cost extension)
Project Title: Exercise and Intensive Vascular Risk Reduction in Preventing Dementia
Project Number: R01 AG049749
Role in Project: Co-Investigator
Duration of Project: 02/2016-01/2021
Project Title: Hypertension, intracranial pulsatility and brain Aβ accumulation in older adults
Project Number: R01 AG05333
Role in Project: Co-Investigator
Duration of Project: 09/2017-08/2022
Project Title: Contribution of Plasmablasts in the Conversion of Transvers Myelitis to Multiple Sclerosis
Project Number: R01 NS10241
Role in Project: Collaborator
Duration of Project: 04/2018-03/2023
Stowe, AM, Ireland, SJ, Ortega, SB, Chen, D, Huebinger, RM, Tarumi, T, Harris, TS, Cullum, CM, Rosenberg, R, Monson, NL, and Zhang, R (2017). Lymphocytes and brain Aβ burden in patients with mild cognitive impairment. J Neuroinflammation 14(1):149. PMID: 28750671 (2017 IF: 5.2)
Selvaraj, UM, Zuurbier, KR, Whoolery, CW, Plautz, EJ, Chambliss, KL, Kong, X, Zhang, S, Kim, SH, Katzenellenbogen, BS, Katzenellenbogen, JA, Mineo, C, Shaul, PW, and Stowe, AM (2018). Selective non-nuclear estrogen receptor activation decreases stroke severity and promotes functional recovery in mice. Endocrinology 159 (11): 3848-3859 (2017 IF: 4.0)
Ortega, SB, Pandiyan, P, Windsor J, Torres, VO, Selvaraj, UM, Lee, A, Morriss, M, Tian, F, Raman, L, and Stowe, AM (2019). A pilot study identifying brain-targeting adaptive immunity in pediatric Extracorporeal Membrane Oxygenation (ECMO) patients with acquired brain injury. Critical Care Med 47(3):e206-e213 (2015 IF: 7.4)
Yanev, P, Poinsatte, K, Hominick, D, Khurana, N, Zuurbier, KR, Berndt, M, Plautz, EJ, Dellinger, MT, and Stowe, AM (2019). Impaired meningeal lymphatic vessel development worsens stroke outcome. J Cereb Blood Flow Metab ePub Jan 29 (2018 IF: 6.0
Poinsatte, K, Smith, EE, Torres, VO, Ortega, SB, Huebinger, RM, Cullum, CM, Monson, NL, Zhang, R, and Stowe, AM (2019). T and B cell subsets differentially correlate with amyloid deposition and neurocognitive function in patients with amnestic mild cognitive impairment after one year of physical activity. Exercise Immunology Review 25:34-49 (2014 IF: 9.9)
Szabo-Reed, AN, Vidoni, E, Binder, EF, Burns, J, Cullum, CM, Gahan, WG, Hynan, LS, Kerwin, DR, Rossetti, H, Stowe, AM, Vongpatanasin, W, Zhu, DC, Zhang, R, and Keller, J (2019). Rationale and methods for a multicenter clinical trial assessing exercise and intensive vascular risk reduction in preventing dementia (rrAD Study). Contemporary Clinical Trials ePub Feb. 28, 2019 (2017 IF:2.7)
Tarumi, T, Rossetti, H, Thomas, BP, Harris, T, Tseng, BY, Turner, M, Wang, C, German, Z, Martin-Cook, K, Stowe, AM, Womack, KB, Mathews, D, Kerwin, DR, Hynan, L, Diaz-Arrastia R, Lu, H, Cullum, MC, and Zhang, R (2019). Exercise Training in Amnestic Mild Cognitive Impairment: A 1-Year Randomized Controlled Trial. J Alzheimers Dis. ePub Aug. 8, 2019 (2016 IF:3.9)
Poinsatte, K, Ortega, SB, Selvaraj, UM, Meeuwissen, AJM, Kong, X, Plautz, EJ, Monson, NL, Zhang R, and Stowe, AM (2019). Detraining ablates exercise-induced modulation of the immune system after stroke. Conditioning Medicine, 2(2):50-60.
Poinsatte, K, Betz, D, Torres, VO, Ajay, AD, Merza, S, Selvaraj, UM, Plautz, EJ, Kong, X, Gokhale, S, Meeks, JP, Ramirez, DMO, Goldberg, MP, and Stowe, AM (2019, in press). Visualization and quantification of post-stroke neural connectivity and 1 neuroinflammation using serial two-photon tomography in the whole mouse brain. Frontiers in Neurosci (2017 IF: 3.6)