Kristian Doyle
Associate Professor, BIO5 Institute
Associate Professor, Immunobiology
Associate Professor, Neurology
Associate Professor, Neuroscience - GIDP
Associate Professor, Neurosurgery
Associate Professor, Psychology
Research Scientist
Primary Department
Department Affiliations
(520) 626-7013
Work Summary
Approximately 795,000 Americans suffer a stroke each year, and 400,000 will experience long-term disability. The number of stroke survivors in the population is expected to double by 2025. Currently, treatments for stroke patients are limited to tissue plasminogen activator (TPA), but its use is limited to the first few hours after stroke. Therefore, the goal of our research is to develop new therapeutics that can promote repair and recovery in this rapidly growing population.
Research Interest
The Doyle lab investigates the role of the immune system in causing dementia after stroke. Up to 30% of stroke patients develop dementia in the months and years after their stroke and we are testing the hypothesis that in some patients this is due to a chronic inflammatory response that persists at the site of the stroke infarct. We suspect that in the weeks, months and possibly years after stroke, neurotoxic inflammatory mediators, including T cells, cytokines and antibodies, leak out of the stroke infarct and cause bystander damage to the surrounding tissue, which then both impairs recovery, and in some instances leads to cognitive decline. In support of this hypothesis we have data that demonstrates that inflammation persists for months at the site of the infarct after stroke, and that a single stroke can directly lead to the development of immune-mediated delayed cognitive deficits. We are currently in the process of targeting different components of the prolonged inflammatory response to stroke to determine if post stroke dementia can be treated by selectively ablating individual immune mediators such as B lymphocytes, T lymphocytes, and CCR2. Keywords: Neuroinflammation, stroke, dementia, Alzheimer's disease


Bartlett, M. J., Flores, A. J., Dollish, H. K., Farrell, D. C., Parent, K. L., Besselsen, D. G., Heien, M. L., Doyle, K., Cowen, S. L., Steece-Collier, K., Sherman, S. J., & Falk, T. (2017). Neuroplastic mechanism of sub-anesthetic ketamine treatment to reduce development of L-DOPA-induced dyskinesia. Science Translational Medicine.
BIO5 Collaborators
David G Besselsen, Kristian Doyle
Doyle, K. P., Yang, T., Lessov, N. S., Ciesielski, T. M., Stevens, S. L., Simon, R. P., King, J. S., & Stenzel-Poore, M. P. (2008). Nasal administration of osteopontin peptide mimetics confers neuroprotection in stroke. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 28(6), 1235-48.

Osteopontin (OPN), a large secreted glycoprotein with an arginine, glycine, aspartate (RGD) motif, can bind and signal through cellular integrin receptors. We have shown previously that OPN enhances neuronal survival in the setting of ischemia. Here, we sought to increase the neuroprotective potency of OPN and improve the method of delivery with the goal of identifying a treatment for stroke in humans. We show that thrombin cleavage of OPN improves its ability to ligate integrin receptors and its neuroprotective capacity in models of ischemia. Thrombin-cleaved OPN is a twofold more effective neuroprotectant than the untreated molecule. We also tested whether OPN could be administered intranasally and found that it is efficiently targeted to the brain via intranasal delivery. Furthermore, intranasal administration of thrombin-treated OPN confers protection against ischemic brain injury. Osteopontin mimetics based on the peptide sequences located either N or C terminal to the thrombin cleavage site were generated and tested in models of ischemia. Treatment with successively shorter N-terminal peptides and a phosphorylated C-terminal peptide provided significant neuroprotection against ischemic injury. These findings show that OPN mimetics offer promise for development into new drugs for the treatment of stroke.

Doyle, K. P. (2016). Unraveling the pathophysiology of chronic stroke lesions could yield treatments for stroke-related dementia. Future Neurology, 11(1), 1-4.
Han, J., Pollak, J., Yang, T., Siddiqui, M. R., Doyle, K. P., Taravosh-Lahn, K., Cekanaviciute, E., Han, A., Goodman, J. Z., Jones, B., Jing, D., Massa, S. M., Longo, F. M., & Buckwalter, M. S. (2012). Delayed administration of a small molecule tropomyosin-related kinase B ligand promotes recovery after hypoxic-ischemic stroke. Stroke; a journal of cerebral circulation, 43(7), 1918-24.

Stroke is the leading cause of long-term disability in the United States, yet no drugs are available that are proven to improve recovery. Brain-derived neurotrophic factor stimulates neurogenesis and plasticity, processes that are implicated in stroke recovery. It binds to both the tropomyosin-related kinase B and p75 neurotrophin receptors. However, brain-derived neurotrophic factor is not a feasible therapeutic agent, and no small molecule exists that can reproduce its binding to both receptors. We tested the hypothesis that a small molecule (LM22A-4) that selectively targets tropomyosin-related kinase B would promote neurogenesis and functional recovery after stroke.

Doyle, K. P., Nguyen, T. V., Mckay, B. S., Konhilas, J. P., Day, A. W., Figueroa, A., Hayes, M., Constantopoulos, E., Zbesko, J., Frye, J., & Chung, A. (2018). Liquefaction of the brain following stroke shares a similar molecular and morphological profile with atherosclerosis and mediates secondary neurodegeneration in an osteopontin dependent mechanism. eNeuro.