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Neurovascular Surgery Research

Research at The University of Chicago Neurovascular Surgery Program builds upon a strong and deep legacy for nearly a century. Percival Bailey, MD, came to the University of Chicago from Boston in the 1920’s and his contributions defined the current classification of vascular tumors and malformations of the brain. More recently, Sean Mullan, MD, clarified the angioarchitecture of cerebral arteriovenous malformations and fistulae, and Bryce Weir discovered the basic pathobiologic mechanisms of cerebral vasospasm after subarachnoid hemorrhage. These pioneering contributions continue to influence the clinical management of scores of patients to this date. Today, the Neurovascular Surgery research teams, led by Issam Awad, MD, MSc, MA (hon), carry this rich tradition with groundbreaking discoveries and the mentoring of clinician scientists. The research bridges scientific discoveries to the care of patients in the clinic and operating room.

Biology of Cerebrovascular Malformations

Current research is focused on the molecular mechanisms of cerebral cavernous malformation (CCM) genesis, a common vascular anomaly affecting 0.5 percent of the population, and predisposes people to a lifetime risk of hemorrhagic stroke and epilepsy. Funded by the National Institutes of Health (NIH) for the past decade, the laboratory includes Research Associate (Assistant Professor) Robert Shenkar, PhD, and Research Scientist Changbin Shi, MD, PhD, who work under Dr. Awad’s oversight, are currently engaged in the characterization of experimental CCM lesions in mutant mice, using high field MR techniques and in molecular dissection of animal and human CCM lesions from excised surgical specimens. Lesional cells are microdissected to test the hypothesis that somatic mutations are present in developing lesions, at the earliest stages of lesion genesis and in subsequent stages of CCM lesion maturation. The laboratory has characterized an oligoclonal immune response in the human CCM lesions, and is testing the hypothesis that an antigenic trigger is responsible for lesion progression. Signaling pathways related to CCM genes are being investigated for mechanistic role and potential therapeutic targeting. Mentored trainees are exposed to the range of cell and molecular biology techniques including immunohistochemistry, cellular laser microdissection, in vivo and in vitro high field MRI for phenotypic characterization, and RNA and DNA extraction from microdissected cells, cloning, sequencing and recombinant antibody synthesis. Focused projects are available for individual trainees, as well as extensive supervision in mentored penmanship and grantsmanship. The laboratory team meets weekly for data review and guidance of ongoing projects.

Genetically engineered CCM lesion in mutant mouse
Genetically engineered CCM lesion in mutant mouse. Right, lesion localized by high field (14T) MRI in the mouse brain. Left, correlative histology, identical to human lesions.

Novel Therapies for Hemorrhagic Stroke

Intracranial hemorrhages account for approximately one sixth of all strokes, yet they result in disproportionately catastrophic outcomes, accounting for half of stroke-related deaths, disability and costs of care. The great majority of hemorrhagic strokes consist of intracerebral hemorrhage (ICH) and intraventricular hemorrhage (IVH), which have been associated with case mortality rates exceeding 50 percent in community-based studies, and case disability rates exceeding 80 percent. Unlike the more common ischemic strokes, for which significant therapeutic advances have been made through acute thrombolysis and several effective medical and surgical modalities for secondary stroke prevention, there is not currently a single proven treatment to prevent death or to alleviate the disability from ICH and IVH. Our team has helped develop techniques of minimally invasive evacuation of IVH and ICH, which hold great promise to change the clinical management of these devastating strokes.

Dr. Awad is currently the co-Principal Investigator on a recently launched NIH-funded Phase III Clinical Trial assessing intraventricular catheter administered thrombolysis for IVH. He is overseeing 50 surgical investigators around the world in a Phase III trial funded by the NIH (www.cleariii.com). He investigates minimally invasive interventions for ICH, now in Phase II clinical trial (www.mistietrial.com). Dr Awad oversees a team including Jennifer Jaffe, MPH, Clinical Trial Manager, clinical research nurses and biostatisticians, working closely with trial management centers and investigators throughout the world. Two to three mentored trainees are exposed to modern clinical trial design and execution, and are involved in focused projects related to analysis of catheter placement, review of surgical protocols of enrolled subjects, and clot clearance kinetics in relation to thrombolysis dose and catheter location. The hemorrhagic stroke research team meets weekly to review trial progress, and to guide individual sub-projects, including those by mentored trainees.

Casted IVH Before Intraventricular ThrombolysisCasted IVH After Intraventricular Thrombolysis
Casted IVH before (Left) and after (right) intraventricular thrombolysis. The casts (red) are rendered based on computed tomographic scan data. Ventricular drainage catheters (blue) are placed using image guidance.