• The Zipfel Cerebrovascular Lab

    Neurosurgery -- Washington University in St. Louis

  • OUR MISSION

    To understand the mechanisms driving acute and chronic cerebrovascular diseases, identify new molecular targets, and develop novel therapies that will improve the lives of our patients. We have two primary areas of interest: 1) Applying conditioning-based therapy to prevent or reduce secondary brain injury after aneurysmal subarachnoid hemorrhage (SAH); and 2) Understanding the mechanisms of vascular oxidative stress and their contribution to Cerebral Amyloid Angiopathy (CAA) and Alzheimer's disease. We use a combination of molecular, cellular, genetic, and neurobehavioral approaches for our studies. We also translate fundamental discoveries from the lab into early phase clinical trials. Our laboratory is a unique and collaborative working environment embedded within a dynamic interdisciplinary research program called the Hope Center Program for Protein Aggregation and Neurodegeneration. We are located in the BJC Institute of Health -- a state-of-the-art research building that is part of BioMed 21, a Washington University initiative to rapidly translate basic research findings into novel medical therapies.

  • SELECTED PUBLICATIONS

    Aneurysmal Subarachnoid Hemorrhage

    Amyloid-β Dynamics Correlate with Neurological Status in the Injured Human Brain

    Science. 2008 Aug;321(5893):1221-4

     

    We used intracerebral microdialysis to obtain serial brain interstitial fluid samples in patients undergoing invasive intracranial monitoring after acute brain injury. We found a strong positive correlation between changes in brain interstitial fluid Aβ concentrations and neurological status. We also found that brain interstitial fluid Aβ concentrations were lower when other cerebral physiological and metabolic abnormalities reflected depressed neuronal function. Such dynamics fit well with the hypothesis that neuronal activity regulates extracellular Aβ concentrations.

     

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    eNOS Mediates Endogenous Protection Against Subarachnoid Hemorrhage-induced Cerebral Vasospasm

    Stroke 2011. Mar;42(3):776-82

     

    Hypoxic preconditioning (PC) nearly completely prevented subarachnoid hemorrhage-induced reduction in nitric oxidate availability, vasospasm and neurological deficits. This protection was lost in wild-type mice treated with the nitric oxide synthase inhibitor, L-NAME, and in eNOS-null mice. These data indicate endogenous protective mechanisms against vasospasm exist, are powerful, can be induced by PC, and are critically dependent on eNOS-derived nitric oxide. They also suggest conditioning-based therapy is a promising new strategy to reduce vasospasm and delayed cerebral ischemia after subarachnoid hemorrhage.

     

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    HIF-1α Mediates Isoflurane-Induced Vascular Protection in Subarachnoid Hemorrhage

    Ann Clin Transl Neurol 2015. Apr;2(4):325-37

     

    Isoflurane postconditioning reduced cerebral vasospasm, microvessel thrombosis, microvascular dysfunction, and neurological deficits in wild-type mice. Isoflurane-induced protection against subarachnoid hemorrhage-induced delayed cerebral ischemia was attenuated in 2ME2-treated wild-type mice and endothelial cell-specific HIF-1α-null mice. These results implicate cerebral vessels as a key target for the brain protection afforded by isoflurane postconditioning, and HIF-1α as a critical mediator of this vascular protection. They also identify isoflurane postconditioning as a promising novel therapeutic for subarachnoid hemorrhage.

     

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    Minocycline protects against delayed cerebral ischemia after subarachnoid hemorrhage via MMP‐9 inhibition

    Ann Clin Transl Neurol. 2017 Oct;4(12):865-876

     

    We demonstrated that MMP-9 expression and activity are increased after subarachnoid hemorrhage in mice. We also showed that genetic (MMP-9 knockout) and pharmacological (minocycline) inhibition of MMP-9 decreases vasospasm and neurobehavioral deficits in mice, and that minocycline administration to MMP-9 knockout mice does not yield additional protection. We also showed that minocycline reduces vasospasm in rabbits. These data indicate MMP-9 is a key player in the pathogenesis of subarachnoid hemorrhage-induced delayed cerebral ischemia, and that minocycline has promise as a novel MMP-9 directed therapy for subarachnoid hemorrhage patients.

     

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    A novel fluorescent imaging technique for assessment of cerebral vasospasm after experimental subarachnoid hemorrhage

    Sci Rep. 2017 Aug;7(1):9126

     

    We applied ROX SE fluorescent imaging to our mouse model of subarachnoid hemorrhage and found that this novel imaging technique is qualitatively and quantitatively superior to India ink-gelatin casting for the assessment of cerebral vasospasm, while also permitting outstanding immunohistochemical examination of non-vasospasm components of secondary brain injury.

     

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    A Phase I proof-of-concept and safety trial of sildenafil to treat cerebral vasospasm following subarachnoid hemorrhage

    J Neurosurg. 2016 Feb;124(2):318-27

     

    Subarachnoid hemorrhage patients with angiographically confirmed vasospasm were treated with intravenous silenafil and monitored for safety and efficacy. Of the 12 treated patients, 8 (67%) had a positive angiographic response, 3 (60%) in the low-dose group and 5 (71%) in the high-dose group. The largest degree of vessel dilation was an average of 0.8 mm (range 0-2.1 mm). This corresponded to an average percentage increase in vessel diameter of 62% (range 0%-200%). Results from this Phase I clinical trial showed sildenafil is safe and well tolerated in the setting of subarachnoid hemorrhage and suggest a positive impact on vasospasm.

     

    For details, click here.

  • SELECTED PUBLICATIONS

    Cerebral Amyloid Angiopathy (CAA) / Alzheimer's Disease

    Cerebrovascular dysfunction in amyloid precursor protein transgenic mice: contribution of soluble and insoluble amyloid-beta peptide, partial restoration via gamma-secretase inhibition

    J Neurosci. 2008 Dec;28(50):13542-50

     

    We showed that a strong correlation between CAA severity and vessel reactivity exists in Tg2576 mice; a surprisingly small amount of CAA produces marked reduction or complete loss of vessel function; CAA-induced vasomotor impairment results from dysfunction rather than loss or disruption of vascular smooth muscle cells; and acute depletion of Aβ improves vessel function in young and to a lesser degree aged Tg2576 mice. These results suggest soluble and insoluble Aβ causes vasomotor impairment, that mechanisms other than Aβ-induced alteration in vessel integrity are responsible, and that anti-Aβ therapy may have beneficial effects on vascular as well as parenchymal amyloid.

     

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    Contribution of reactive oxygen species to cerebral amyloid angiopathy, vasomotor dysfunction, and microhemorrhage in aged Tg2576 mice

    Proc Natl Acad Sci U S A. 2015 Feb;112(8):E881-90

     

    We showed that the NADPH oxidase inhibitor, apocynin, and the free radical scavenger, tempol, reduce oxidative stress and improve vessel reactivity in aged Tg2576 mice; the improved cerebrovascular function is due to reduction in CAA formation and a decrease in CAA-induced vasomotor impairment; and antioxidant therapies attenuate CAA-related microhemorrhage. These results indicate oxidative stress is a key contributor to CAA formation, CAA-induced vessel dysfunction, and CAA-related microhemorrhage, and suggest that NADPH oxidase-derived oxidative stress is a promising therapeutic target for patients with CAA and Alzheimer's disease.

     

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    Resorufin analogs preferentially bind cerebrovascular amyloid: potential use as imaging ligands for cerebral amyloid angiopathy

    Mol Neurodegener. 2011 Dec;6:86

     

    We demonstrated that the phenoxazine derivative, resorufin, preferentially binds CAA (arrowheads) over neuritic plaques (arrows) in aged Tg2576 mice. We also found that resorufin staining was predominantly noted in amyloid-laden vessels in postmortem Alzheimer's brain tissues, and that resorufin selectively visualizes CAA in live Tg2576 mice when topically administered. Resorufin analogs are the fist class of amyloid dye that discriminate between cerebrovascular and neuritic forms of amyloid. This binding selectivity suggests resorufin analogs have great potential as a CAA-specific amyloid tracer that could permit non-invasive detection and quantification of CAA in live patients.

     

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    Heparan sulfate proteoglycans (HSPG) mediate Aβ-induced oxidative stress and hypercontractility in cultured vascular smooth muscle cells (VSMC)

    Mol Neurodegener. 2016 Jan;11:9

     

    We demonstrated that pharmacological depletion of HSPG in cultured VSMC mitigates Aβ40- and Aβ42-induced oxidative stress. We also found that Aβ40 (but not Aβ42) causes a hypercontractile phenotype in cultured VSMC that likely results from a HSPG-mediated augmentation in intracellular Ca(2+) activity. Taken together, our data indicate that HSPG are critical mediators of Aβ-induced oxidative stress and Aβ40-induced VSMC dysfunction, and suggests HSPG may play a critical core in CAA-induced cerebrovascular dysfunction and CAA pathogenesis.

     

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    Cerebral amyloid angiopathy (CAA) increases susceptibility to infarction after focal cerebral ischemia in Tg2576 mice

    Stroke. 2014 Oct;45(10):3064-9.

     

    We demonstrated that aged Tg2576 mice have more severe cerebrovascular dysfunction that is CAA dependent, have greater cerebral blood flow compromise during and immediately after middle cerebral artery occlusion, and develop larger infarctions after middle cerebral artery occlusion. These data indicate CAA induces a more severe form of cerebrovascular dysfunction than soluble Aβ alone, leading to intra- and postischemic cerebral blood flow deficits that ultimately exacerbate cerebral infarction.

     

    For details, click here.

    Passive immunotherapy targeting amyloid-β reduces cerebral amyloid angiopathy and improves vascular reactivity

    Brain. 2016 Feb;139(Pt 2):563-77.

     

    Chronic administration of the anti-Aβ40 specific antibody, ponezumab, reduced Aβ accumulation both in leptomeningeal and brain vessels in aged Tg2576 mice. Acute administration of ponezumab triggered a significant and transient increase in interstitial fluid Aβ40 levels in aged Tg2576 mice. A beneficial effect on vascular reactivity following acute administration of ponezumab was also noted, even in vessels where there was severe CAA. These data favor a mechanism that involves rapid removal and/or neutralization of Aβ species that may otherwise be detrimental to normal vessel function.

     

    For details, click here.

  • SELECTED EXPERIMENTAL TECHNIQUES

    We use a complementary set of molecular, cellular, genetic, and neurobehavioral approaches for our studies

    Mouse models of amyloidosis

    Aged Tg2576, PSAPP, and 5xFAD:APOE4 transgenic mice are used to study CAA (arrows) and neuritic plaques (arrowheads) that are imaged with congo red derivative dyes like X34.

    Mouse model of subarachnoid hemorrhage

    Endovascular perforation of the left internal carotid artery bifurcation (arrow) produces experimental subarachnoid hemorrhage in mice and rats.

    Cerebrovascular Function

    Pial arteriole vasoreactivity to hypercapnia and topical vasoactive agents is assessed via open cranial window technique in live mice.

    Cerebral Vasospasm

    Subarachnoid hemorrhage-induce cerebral vasospasm is quantified via India ink-gelatin casting (circles) or ROX SE fluorescent imaging.

    Smooth Muscle Cell Contractility

    Contractility of cultured human-derived vascular smooth muscle cells is assessed via area measurements of cells (inset) following exposure to KCl and/or Abeta.

    Neurobehavior

    Complementary set of neurobehavioral tests are utilized including Novel Object Recognition, Novel Object Location, Y-maze, Burrowing Behavior, and Morris Water Maze.

    Functional Connectivity by fMRI

    Resting state functional MRI (fMRI) techniques are used to assess Functional Connectivity of brain networks after acute and chronic brain injury

  • THE PRINCIPAL INVESTIGATOR

    Gregory J. Zipfel, MD

    Dr. Zipfel grew up in Peoria, IL, the son of two teachers. He attended college at the University of Illinois and then graduated with honors from Northwestern University Medical School. After completing his residency and fellowship training at the University of Florida and the University of Miami, he returned to the Midwest in 2004 to begin his career as a vascular neurosurgeon-scientist at Washington University in St. Louis. Dr. Zipfel is a passionate clinician, scientist, educator, and mentor. He particularly enjoys the opportunity to care for patients with cerebrovascular disease while also performing fundamental discovery research with the goal of translating his findings back to the clinic in the hopes of improving patient outcomes in the future.

  • OUR TEAM

    Vivian, Ernie, Deepti, Greg, Jane, Sarah, and Julian (left to right)

    Celebrating Deepti's American Heart Association Post-Doctoral Research Grant -- Congratulations Deepti!!

  • LAB MEMBERS

    We are a collaborative and diverse group of scientists driven to making fundamental discoveries in the lab and rapidly translating these insights to the clinic.  

    Gregory J. Zipfel

    Principal Investigator

    Dr. Zipfel's lab has been continuously funded by the NIH since 2005 and currently includes two active R01's. He is a passionate mentor with a long track record of successful mentees -- a group that includes 5 neurosurgical, 1 neurology, and 1 anesthesiology faculty; 8 post-doctoral fellows; 13 medical students; and 11 undergraduates.

    Deepti Diwan

    Post-Doctoral Fellow

    Dr. Diwan received her Ph.D. in genome profiling from Saitama University in Saitama City, Japan. She joined the Zipfel lab in 2017. She focuses her research on deciphering the molecular mechanisms underlying hypoxic post-conditioning in subarachnoid hemorrhage.

    Julian Clarke

    Graduate Student

    Julian is a Washington University medical student who joined the lab in 2017 and is pursing a combined MD/MA degree. He focuses his research on examining the impact of subarachnoid hemorrhage and hypoxic post-conditioning on the functional connectivity of brain networks.

    Umeshkumar Athiraman

    Assistant Professor, Anesthesiology

    Dr. Athiraman was recruited to the Anesthesiology Department at Washington University in St. Louis in 2015 and joined the Zipfel lab soon thereafter. He directs clinical anesthesia for neurosurgery and is the Program Director for the Neuroanesthesia fellowship. His research focuses on applying anesthetic conditioning to subarachnoid hemorrhage -- as a therapeutic and as a means for discovering new druggable molecular targets.

    Ananth Vellimana

    Resident, Neurosurgery

    Dr. Vellimana trained at All India Institute of Medical Sciences for medical school, completed a post-doctorate in the Zipfel lab, and currently is a neurosurgery chief resident at Washington University in St. Louis. He focuses his research on elucidating the mechanisms underlying subarachnoid hemorrhage-induced delayed cerebral ischemia and hypoxic conditioning-induced brain protection in subarachnoid hemorrhage.

     

    Jogender Mehla

    Senior Scientist

    Dr. Mehla completed his PhD at All India Institute of Medical Sciences and currently is completing a Post-Doctoral Research Fellowship in the labs of Drs. Robert McDonald and Majid Mohajerani at the Canadian Centre for Behavioural Neuroscience, University of Lethbridge. Dr. Mehla is joining the Zipfel lab in early 2019, and his research will focus on determining the role and elucidating the mechanisms of vascular oxidative stress and cerebral amyloid angiopathy in Alzheimer's disease.

    Jane Yuan

    Medical Student

    Jane is a medical student at Washington University who joined the Zipfel lab in 2017. She focuses her research on elucidating the molecular mechanisms by which hypoxic postconditioning induces neurovascular protection in subarachnoid hemorrhage.

    Vivian Lee

    Medical Student

    Vivian is a medical student at Washington University who joined the Zipfel lab in 2017. She focuses her research on elucidating the molecular mechanisms by which hypoxic postconditioning induces neurovascular protection in subarachnoid hemorrhage.

    Sarah Zhang

    Research Technician

    Sarah has decades of experience as a research technician with varied expertise. She joined the Zipfel lab in 2017. She oversees breeding of all genetically modified mice and assists with a number of other experimental techniques.

    Ernesto Gonzalez

    Research Technician

    Ernie is a master experimental animal surgeon who is the lead surgeon for the In Vivo Animal Surgery Core of Washington University's Hope Center. He has been a member of the Zipfel lab since 2006.

  • Alumni

    We are extremely proud of all past members of the Zipfel lab 

    Terry Kummer

    Assistant Professor, Neurology

    Washington University in St. Louis

    Lab years: 2010-2015

    Position: Instructor

     

    Matthew Reynolds

    Assistant Professor, Neurosurgery

    Loyola University

    Lab years: 2012-2014

    Position: Post-doctorate

     

    Chad Washington

    Assistant Professor, Neurosurgery

    University of Mississippi

    Lab years: 2012-2014

    Position: Post-doctorate

    Andrew Johnson

    Medical Science Liaison,

    Mallinckrodt Pharmaceuticals

    Lab years: 2012-2014

    Position: Post-doctorate

     

    Meng-liang Zhou

    Assistant Professor, Neurosurgery

    Nanjing University, China

    Lab years: 2008-2010

    Position: Post-doctorate

     

    Spiros Blackburn

    Associate Professor, Neurosurgery

    University of Texas-Houston

    Lab years: 2008-2009

    Position: Post-doctorate

    Hyung-Jin Lee

    Assistant Professor, Neurosurgery

    Catholic University, South Korea

    Lab years: 2008-2009

    Position: Post-doctorate

    Diane Aum

    Resident, Neurosurgery

    Washington University in St. Louis

    Lab years: 2016-2017

    Position: Medical Student

     

    Ridhima Guniganti

    Resident, Neurosurgery

    Washington University in St. Louis

    Lab years: 2016-2017

    Position: Medical Student

    Julia Suggs

    Medical Student,

    Washington University in St. Louis

    Lab year: 2017

    Position: Medical Student

    Brent Bruck

    Resident, Ophthalmology

    Washington University in St. Louis

    Lab years: 2015-2016

    Position: Medical Student

    Matt Mollman

    Physician, Emergency Medicine

    Austin, TX

    Lab years: 2013-2014

    Position: Medical Student

    Bhuvic Patel

    Resident, Neurosurgery

    Washington University in St. Louis

    Lab years: 2012-2014

    Position: Medical Student

    Jacob Greenberg

    Resident, Neurosurgery

    Washington University in St. Louis

    Lab years: 2010-2011

    Position: Medical Student

    David Kim

    Resident, Anesthesiology

    Rush University

    Lab years: 2010-2011

    Position: Medical Student

     

    Eric Milner

    Instructor,

    Arizona State University

    Lab years: 2006-2014

    Position: Graduate Student

     

    Molly Lawrence

    Medical Student,

    Northwestern University

    Lab years: 2015-2018

    Position: Undergraduate

     

    Eunjae Lee

    Medical Student,

    Temple University

    Lab years: 2012-2016

    Position: Undergraduate

     

    Emily Lin

    Medical Student,

    Medical College of Wisconsin

    Lab years: 2012-2015

    Position: Undergraduate

    James Baek

    MSTP Student,

    Indiana University

    Lab years: 2012-2014

    Position: Undergraduate

     

    Glenn Harris

    Medical Student,

    Vanderbilt University

    Lab years: 2012-2014

    Position: Undergraduate

     

    Michael Harries

    Medical Student,

    University of Chicago

    Lab years: 2010-2013

    Position: Undergraduate

     

    Tej Azad

    Medical Student

    Stanford University

    Lab years: 2010-2013

    Position: Undergraduate

     

    Yan Wang

    Resident, Neurology

    Washington University in St. Louis

    Lab years: 2008

    Position: Undergraduate

    Min Yoo

    Resident, PM&R

    UC-Irvine

    Lab years: 2007-2010

    Position: Undergraduate

  • News

    Medical student, Vivian Lee, receives the Carolyn L. Kuckein Student Research Fellowship Award from the Alpha Omega Alpha National Honor Medical Society to support her research in the Zipfel lab

    August 7, 2018

    St. Louis Magazine highlights the care of a young woman who Dr. Zipfel treated for a ruptured brain AVM

    June 6, 2018

    St. Louis NBC affiliate, KSDK, highlights the care of a 25 year old woman who Dr. Zipfel treated for a ruptured brain AVM

    May 11, 2018

    Neurosurgeon dedicated to making surgeries smaller, less invasive

    June 20, 2016

    Barnes-Jewish Hospital blog highlighting Dr. Zipfel's use of minimally invasive surgical approaches

    February 6, 2012

  • INTERESTED IN JOINING OUR TEAM?

    Please submit a CV and a brief description of your research background and career goals to Gregory J. Zipfel (zipfelg@wustl.edu).

    Post-Doctoral Research Fellow

    We are recruiting a highly motivated Post-Doctoral Research Fellow to join our fast-paced investigative environment. This position will focus on the lab’s R01-funded research program investigating the role and mechanisms of vascular oxidative stress on Alzheimer’s Disease, Cerebral Amyloid Angiopathy, and other forms of dementia. Previous experience in vascular cell culture, vascular biology, animal models of Alzheimer's disease and other neurodegenerative conditions, animal surgery, and advanced ex vivo and in vivo imaging is strongly desired.

    Medical and Undergraduates Students

    Medical students typically enter the lab as a summer research student, many of which ultimately pursue a dedicated research year in the lab. To date, we have mentored 13 medical students -- all of whom have been accepted or are currently applying to highly competitive specialties including neurosurgery.  

     

    Undergraduate students typically enter the lab in the first or second year of their studies and make a multi-year commitment to the lab. To date, the Zipfel Lab has mentored 11 undergraduate students -- all of whom have been accepted or are currently applying to medical school.

  • SUPPORT OUR RESEARCH

    We cannot do it alone...

    If you would like to help us in our quest to develop new treatments for our patients with Brain Aneurysms, Alzheimer's Disease, and Vascular Dementia, please contact:

     

    Jaclyn Stewart Strothmann

    The Foundation for Barnes-Jewish Hospital

    314-286-0450
    Jaclyn.StewartStrothmann@bjc.org