Dr. Donald Miller
Department of Pharmacology & Therapeutics
Kleysen Institute for Advanced Medicine
University of Manitoba
General Research Themes: Neuropharmacology; blood-brain barrier function; drug delivery
The brain capillaries that form the blood-brain barrier (BBB) have a unique, and often under-appreciated role in brain function. Under normal conditions, the BBB restricts the passage of most compounds between the blood and the brain extracellular fluid, thus ensuring a proper environment for the receiving, processing and sending of neuronal signals. However, in many neurological conditions such as multiple sclerosis, neuro-AIDS, stroke, brain tumors and brain trauma, the BBB becomes compromised. Understanding the cellular mechanisms involved in the altered BBB permeability observed during these pathophysiological conditions may provide insight into better treatments for these diseases. In addition, while the BBB has a protective role, restricting passage of compounds from the blood into the brain, it represents an obstacle for many potential therapeutic agents. Thus, identification of strategies for enhancing drug transport and permeability in the BBB is necessary to optimize the efficacy of drugs for treating central nervous system diseases. And finally, as the cellular interface between the blood and the extracellular environment of the brain, the brain capillaries represent an important relay point for the transfer of chemical signals from the periphery to the brain.
Research in my laboratory encompasses all three of the aspects identified above. Examples of ongoing research projects include:
-Examination of blood-brain barrier changes during brain tumor development and identification of methods for increasing the delivery of chemotherapeutic agents in the brain.
-Identification and characterization of drug efflux transport proteins in the blood-brain barrier and their impact on drug delivery to the brain
-Effect of inflammatory stimuli on the activation of brain microvessel endothelial cells
Cell culture, biochemical, molecular and functional assessment of brain endothelial cell function, in vitro and in vivo imaging techniques
Selected Publications (86 total publications; 5 issued patents; H-index 37)
1. Rezaeian A, Korolainen M, Odero G, Miller DW, Kauppinen TM. Poly(ADP-ribose) polymerase-1 regulates microglia mediated degradation of endothelial tight junction integrity. Neurochem. Int. In Press, Epub April 28th 2017
2. M. Norouzi, B. Nazari, and D.W. Miller. (2016). Injectable hydrogel-based drug delivery systems for local cancer therapy. Drug Disc Today. 21, 1835-1849.
3. Z. Sun, M. Worden, J.A. Thliveris, S. Hombach-Klonisch, T. Klonisch, J. van Lierop, T. Hegmann, and D.W. Miller. (2016). Biodistribution of negatively charged iron oxide nanoparticles (IONPs) in mice and enhanced brain delivery using lysophosphatidic acid (LPA). Nanomed. Nanotech. Biol. Med. 12, 1775-1784.
4. H.M. Aukema, T. Winter, A. Ravandi, S. Dalvi, D.W. Miller, and Grant M. Hatch. (2016). Generation of bioactive oxylipins from exogenously added arachidonic, eicosapentaenoic and docosahexaenoic acid in primary human brain microvessel endothelial cells. Lipids. 51, 591-599. [PMID: 26439837].
5. S. Dalvi, H.H. Nguyen, N. On, R.W. Mitchell, H.M. Aukema, D.W. Miller, and G.M. Hatch. (2015). Exogenous arachidonic acid mediates permeability of human brain microvessel endothelial cells through prostaglanding E2 activation of EP3 and EP4 receptors. J. Neurochem. 135, 867-879. [PMID: 25865705]
7. Z. Sun, M. Morden, Y. Wroczynskyj, P.K. Manna, J.A. Thliveris, J. van Lierop, T. Hegmann and D.W. Miller. (2016). Differential internalization of brick shaped iron oxide nanoparticles by endothelial cells. J. Mat. Chem. B. 4, 5913-5920.
8. M.D. Laksitorini, P.K. Kiptoo, N.H. On, J.A. Thliveris, D.W. Miller, T.J. Siahaan. (2015). Modulation of intercellular junctions by cyclic-ADT peptides as a method to reversibly increase blood-brain barrier permeability. J. Pharm. Sci. 104, 1065–1075. [PMID: 25640479; PMCID: PMC4442687]
9. T. Bera, E.J. Freeman, J.A. McDonough, R.J. Clements, A. Aladlaan, D.W. Miller, C. Malcuit, T. Hegmann, and E. Hegmann. (2015). Liquid crystal elastomer microspheres as 3D cell scaffolds supporting the attachment and proliferation of myoblasts. ACS Appl Mater Interfaces. E-Pub. 2015 Jun 15. [PMID: 26075811]
10. Z. Sun, M. Worden, Y. Wroczynskyj, V. Yathindranath, J. van Lierop, T. Hegmann, and D.W. Miller, (2014). Magnetic field enhanced convective diffusion of iron oxide nanoparticles in an osmotically disrupted cell culture model of the blood-brain barrier. Int. J. Nanomedicine 9, 3013–3026. [PMC4073976; PMID: 25018630]
11. NH. On, P. Kiptoo, T.J. Siahaan, and D.W. Miller. (2014). Modulation of blood-brain barrier (BBB) permeability in mice using synthetic E-cadherin peptide. Mol. Pharm. 11, 974–981. [PMC3993937; PMID: 24495091]
12. N.H. On and D.W. Miller. (2014). Transporter-based delivery of anticancer drugs to the brain: Improving brain penetration by minimizing drug efflux at the blood-brain barrier. Curr. Pharm. Des. 20, 1499–1509. [PMID: 23789953]
Dr. Donald Miller
Areas of research: Neuropharmacology;
blood-brain barrier function; drug delivery
Dr. Donald Miller
Canadian Institutes of Health Research Project Grant – Development of tumor targeted magnetic nanoparticles for killing tumor cells in the brain
Oct 2016- June 2022
Natural Science and Engineering Research Council – Canada (NSERC) – Cellular mechanisms regulating blood-brain barrier permeability
April 2016 – March 2021