My laboratory has spent the past 36 years actively studying the challenges of central nervous system (CNS) drug delivery in disease states. Our scientific and research focus remains the same today, to develop “state of the art” methods/procedures/tools/models for quantifying/studying the in vivo integrity and regulation of the blood brain barrier/neurovascular unit (BBB/NVU), and multi-drug transporters such as P-glycoprotein (mdr1a;PgP) and OATP 1A4 as altered by pathological disease states associated with brain injury (stroke/hypoxia) and acute versus chronic pain (inflammatory and migraine pain). We remain dedicated to our mission of maintaining the strongest basic science research program in drug delivery and drug - drug interactions (DDI) at the BBB while educating and training undergraduate, graduate and post-doctoral fellows and early/new NIH investigators to advance our field. In the course of our research into the molecular, biochemical and pathophysiological mechanisms associated with maintenance and disruption of the blood-brain barrier/neurovascular unit and endothelial cell tight junction proteins and drug transporters, we have been cited by our peers for “paradigm shifting” discoveries and meritorious mentoring of the “next generation” of BBB/NVU researchers. We understand that progress in preventing, diagnosing, or treating diseases of the CNS depends upon understanding the BBB, NVU and DDI. It is often stated, “if we cannot get the drug into the brain we cannot treat a disease of the brain”. As BBB/NVU investigators we have a unique perspective, and responsibility, to address a critical priority; that after a century of developing and testing CNS therapeutics, pharmaceutical and biotech companies remain frustrated at the enormity of problems associated with delivering drugs to the CNS. My laboratory remains focused on addressing this challenge in this exciting proposal on migraine pain from a very promising new and early NIH investigator.
Pathways discovered where BBB tight junction and transporter proteins can be targeted to improve CNS drug delivery in disease states. We continue to help define the concept that the BBB can be targeted through signaling pathways, specific transporters, and/or drug:drug interactions. These identified pathways point to opportunities to enhance drug delivery in disease states associated with pain and hypoxia.
The focus of my research is the blood brain barrier /Neurovascular Unit (BBB/NVU) in health and disease and specifically the effects of inflammatory pain and stroke on the BBB/NVU. The BBB plays a vital role in maintaining brain homeostasis. Composition of the brain interstitial fluid is controlled within a precise range, independent of fluctuations within the blood, allowing optimal neuronal function to occur throughout life. The BBB is situated at the cerebral endothelial cell tight junctions of the cerebral microvessels.
Figure.1. Schematic showing the BBB/Neurovascular unit. Note the association of NVU astrocytes to endothelial cells.
The cerebral endothelial cells form a continuous membrane with no fenestrations, unlike peripheral vessels. The endothelial cells of the BBB are connected via a network of protein tight junctions that create a rate-limiting, high transendothelial resistance (TEER) barrier to paracellular diffusion of solutes. Structurally, tight junctions form a continuous network of parallel, interconnected, intramembrane protein strands, which are composed of an intricate combination of transmembrane and cytoplasmic proteins linked with the actin-based cytoskeleton, allowing the tight junction to form a cell:cell seal while remaining capable of rapid modulation and regulation by specific signaling molecules.
Figure 2. Schematic of the tight junctions of the BBB. Tight junctions consist of three main groups of proteins. They are transmembrane proteins (Claudins, occludin and junctional adhesion molecules), accessory proteins (ZO-1,2,3 to 20) and cytoskeletal structural proteins (actin etc). All three groups interact to maintain the tight junctions (for a more detailed review see Hawkins and Davis, 2005, or Ronaldson and Davis, 2013). These proteins can be modulated via a number of mechanisms. In neuroinflammatory disorders (Alzheimers, Parkinsons and multiple sclerosis), alterations in these proteins contribute to disease progression.