The cerebral vasculature is the crossroads of the brain, the site of nutrient delivery to and waste clearance from the CNS, ion and water homeostasis, and peripheral immune surveillance of the brain and spinal cord. The neurogenic niche is maintained within perivascular spaces, while the cerebral vasculature is the site of tumor cell entry into and migration through the brain, amyloid beta deposition in Alzheimer’s disease and cerebral amyloid angiopathy, cerebral edema formation and resolution after stroke and traumatic brain injury (TBI), and peripheral leukocyte infiltration in multiple sclerosis. Research in my lab centers upon this crossroads of the CNS, seeking to define the ways that different cell types (including astrocytes, endothelial cells, pericytes, vascular smooth muscle cells, and others) function in concert to maintain brain function, and how these interactions break down in the setting of pathology.
Work in my lab can be broken down into three general domains:
Substrates of age-related vulnerability to amyloid beta deposition and development of Alzheimer’s disease
Neurodegenerative diseases such as Alzheimer’s disease are conditions of the aging brain, yet it is unclear what changes occur in the aging brain that render it vulnerable to the mis-aggregation of amyloid beta and the development of neurodegeneration. Over the past 5 years, we have defined a brain-wide paravascular pathway, termed the ‘glymphatic system’ , that functions as the brain’s waste clearance system, eliminating proteins such as amyloid beta and tau (two pathogenic proteins in Alzheimer’s disease) from the brain interstitium. Glymphatic pathway function is impaired in the aging brain, slowing the clearance of amyloid beta. Ongoing work in my lab is seeking to define the cellular and molecular changes that occur in the aging brain that cause the glymphatic pathway fail, and how those changes might be reveres in the prevention or treatment of Alzheimer’s disease.
Defining the mechanism driving the development of post-traumatic neurodegeneration
TBI is an established risk factor for the development of dementia, including Alzheimer’s disease, which incidence of Alzheimer’s doubling among subjects suffering a substantial TBI early in life. More recent clinical data suggests that even mild TBI (concussion), is associated with an increased risk of early onset dementia. However, it is unclear what takes place in the young post-traumatic brain that appears to set the stage for neurodegeneration later in life. We have reported that after experimental TBI, glymphatic pathway function is impaired, which appears to be underpinned by mis-regulation of an astroglial water channel, aquaporin-4 (AQP4). Ongoing work in my lab is attempting to define the role that AQP4 mis-regulation after TBI has in promoting the aggregation of the protein tau into neurofibrillary tangles and accelerating neurodegeneration in the post-traumatic brain. We are further evaluating whether targeting AQP4 pharmacologically can slow or halt the development of post-traumatic neurodegeneration.
Improving neurotherapeutics delivery to the CNS, through or around the blood brain barrier
The blood brain barrier (BBB) presents a substantial obstacle for the treatment of disease in the CNS. Particularly in the case of recently developed biological therapeutics (such as recombinant enzymes or designer antibodies), un-aided transit through the blood brain is for practical purposes impossible. Several approaches to circumventing the BBB have been developed and are either in clinical use or are under development, including osmotic BBB disruption pioneered by Dr. Ed Neuwelt here at OHSU, intrathecal or intracerebroventricular drug delivery through the cerebrospinal fluid (CSF), or through the use of ‘trojan horse’ strategies to coopt BBB import receptors to transport drug into the brain. However, once these macromolecular therapeutics are able to cross or bypass the BBB, little is known about the physiological and pathophysiological factors that influence drug distribution through the brain parenchyma. Work within my group is seeking to define what biological processes govern CSF and interstitial fluid circulation through the brain and how these processes can be modulated to improve pharmaco-distribution through the CNS.Read more
Areas of interest
- Alzheimer's disease
- Traumatic brain injury
- Blood brain barrier
- Cerebrospinal fluid circulation
- Cerebral blood flow regulation
- Astrocyte cell biology
- Glympahtic system physiology
- Ph.D., Oregon Health & Science University Oregon United States 2009
- B.S., University of Washington Washington United States 2003
- Postdoctoral Fellowship, Center for Translational Neuromedicine, University of Rochester Medical Center 2010 - 2012
Honors and awards
- 2006 - Vertex Pharmaceuticals Scholarship
- 2006 - OHSU Brain Institute Neurobiology of Disease Graduate Student Fellowship
- 2007 - NRSA F31 Predoctoral Fellowship
- 2007 - American Heart Association Predoctoral Fellowship; awarded but declined in lieu of NRSA fellowship
- 2010 - T32 Neuroinflammation and Glial Cell Biology Training Grant Postdoctoral Fellowship
- 2011 - NRSA F32 Postdoctoral Fellowship
- 2013 - Publication in Science named one of ‘Top 10 Breakthroughs of 2013’ by Science
- 2014 - Delivered TED Talk at 2014 TEDMED Conference, San Francisco, CA
- 2015 - AAAS Newcomb Cleveland Prize for Most Outstanding Report Published in Science 2013-2014
- 2015 - Named Allen Distinguished Investigator for Alzheimer’s Disease
Memberships and associations
- American Physiological Society
- American Heart Association/American Stroke Association
- International Society of Cerebral Blood Flow and Metabolism
- International Brain Barrier Society
- International Society to Advance Alzheimer’s Research and Treatment
- New York Academy of Science
- Association of University Anesthesiologists
- Editorial Board, Fluids and Barriers of the CNS
- "The effects of noncoding aquaporin-4 single-nucleotide polymorphisms on cognition and functional progression of Alzheimer's disease." Alzheimer's and Dementia: Translational Research and Clinical Interventions In: , Vol. 3, No. 3, 01.09.2017, p. 348-359.
- "Focal solute trapping and global glymphatic pathway impairment in a murine model of multiple microinfarcts." Journal of Neuroscience In: , Vol. 37, No. 11, 15.03.2017, p. 2870-2877.
- "The Glymphatic System and Brain Interstitial Fluid Homeostasis." Primer on Cerebrovascular Diseases: Second Edition. Elsevier Inc., 2017. p. 17-25.
- "Association of perivascular localization of aquaporin-4 with cognition and Alzheimer disease in aging brains." JAMA Neurology In: , Vol. 74, No. 1, 01.01.2017, p. 91-99.
- "The Emerging Relationship Between Interstitial Fluid-Cerebrospinal Fluid Exchange, Amyloid-β, and Sleep." Biological Psychiatry In: , 01.01.2017.
- "A transcriptome-based assessment of the astrocytic dystrophin-associated complex in the developing human brain." Journal of Neuroscience Research In: , 2017.
- "Regulation of cerebrospinal fluid (CSF) flow in neurodegenerative, neurovascular and neuroinflammatory disease." Biochimica et Biophysica Acta - Molecular Basis of Disease In: , Vol. 1862, No. 3, 01.03.2016, p. 442-451.
- "Methamphetamine induces the release of endothelin." Journal of Neuroscience Research In: , Vol. 94, No. 2, 01.02.2016, p. 170-178.
- "Implications of the discovery of brain lymphatic pathways." The Lancet Neurology In: , Vol. 14, No. 10, 153, 01.10.2015, p. 977-979.
- "Impairment of glymphatic pathway function promotes tau pathology after traumatic brain injury." Journal of Neuroscience In: , Vol. 34, No. 49, 03.12.2014, p. 16180-16193.
- "Impairment of paravascular clearance pathways in the aging brain." Annals of Neurology In: , Vol. 76, No. 6, 01.12.2014, p. 845-861.
- "Effects of traumatic brain injury on reactive astrogliosis and seizures in mouse models of Alexander disease." Brain Research In: , Vol. 1582, 25.09.2014, p. 211-219.
- "The spectrum of neurobehavioral sequelae after repetitive mild traumatic brain injury : A novel mouse model of chronic traumatic encephalopathy." Journal of Neurotrauma In: , Vol. 31, No. 13, 01.07.2014, p. 1211-1224.
- "A novel technique for morphometric quantification of subarachnoid hemorrhage-induced microglia activation." Journal of Neuroscience Methods In: , Vol. 229, 30.05.2014, p. 44-52.
- "The pathophysiology underlying repetitive mild traumatic brain injury in a novel mouse model of chronic traumatic encephalopathy." Surgical Neurology International In: , Vol. 5, No. 1, 01.01.2014.
- "'Hit & Run' model of closed-skull traumatic brain injury (TBI) reveals complex patterns of post-traumatic AQP4 dysregulation." Journal of Cerebral Blood Flow and Metabolism In: , Vol. 33, No. 6, 06.2013, p. 834-845.
- "Evaluating glymphatic pathway function utilizing clinically relevant intrathecal infusion of CSF tracer." Journal of Translational Medicine In: , Vol. 11, No. 1, 107, 01.05.2013.
- "Brain-wide pathway for waste clearance captured by contrast-enhanced MRI." Journal of Clinical Investigation In: , Vol. 123, No. 3, 01.03.2013, p. 1299-1309.
- "A link between glial Ca2+ signaling and hypoxia in aging?" Journal of Cerebral Blood Flow and Metabolism In: , Vol. 33, No. 2, 02.2013, p. 170.
- "Is there a cerebral lymphatic system?" Stroke In: , Vol. 44, No. SUPPL. 1, 01.2013.
- "Sleep drives metabolite clearance from the adult brain." Science In: , Vol. 342, No. 6156, 2013, p. 373-377.
- "Paravascular microcirculation facilitates rapid lipid transport and astrocyte signaling in the brain." Scientific Reports In: , Vol. 3, 2582, 2013.
- "Cerebral arterial pulsation drives paravascular CSF-Interstitial fluid exchange in the murine brain." Journal of Neuroscience In: , Vol. 33, No. 46, 2013, p. 18190-18199.
- "Cognitive deficits and delayed neuronal loss in a mouse model of multiple microinfarcts." Journal of Neuroscience In: , Vol. 32, No. 50, 12.12.2012, p. 17948-17960.
- "A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β." Science Translational Medicine In: , Vol. 4, No. 147, 147ra111, 15.08.2012.
- "Epoxyeicosatrienoic acids are endogenous regulators of vasoactive neuropeptide release from trigeminal ganglion neurons." Journal of Neurochemistry In: , Vol. 115, No. 6, 12.2010, p. 1530-1542.
- "Epoxyeicosanoid signaling in CNS function and disease." Prostaglandins and Other Lipid Mediators In: , Vol. 91, No. 3-4, 04.2010, p. 68-84.
- "Brainstem control of cerebral blood flow and application to acute vasospasm following experimental subarachnoid hemorrhage." Neuroscience In: , Vol. 163, No. 2, 06.10.2009, p. 719-729.
- "Role of soluble epoxide hydrolase in the sex-specific vascular response to cerebral ischemia." Journal of Cerebral Blood Flow and Metabolism In: , Vol. 29, No. 8, 08.2009, p. 1475-1481.
- "Epoxyeicosanoids as mediators of neurogenic vasodilation in cerebral vessels." American Journal of Physiology - Heart and Circulatory Physiology In: , Vol. 296, No. 5, 05.2009.