Neurovascular Surgery Research

A Rich Legacy

Research at The University of Chicago Neurovascular Surgery Program builds up on a strong and deep legacy for nearly a century. Percival Bailey 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 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 Professor Issam Awad 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% of the population, and predisposing 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 faculty, a bioengineer, a computation biologist, three research technical staff, and several predoctoral students and postdoctoral research associates who work under Dr Awad’s oversight. They are currently engaged in the characterization of experimental CCM lesions in mutant mice, using paleo-computed tomography (micro CT), 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 earliest stages of lesions genesis and in subsequent stages of CCM lesion maturation. Lesional studies also help define the disease transcriptome, ie the groups of dysregulated genes causing the pathologic blood vessel failure. The laboratory has characterized an oligoclonal immune response in the human CCM lesions, and identified antigenic triggers responsible for lesion progression. Signaling pathways related to CCM genes are being investigated for mechanistic role and potential therapeutic targeting. The plasma from mouse models and human subjects have been used to identify proteins, circulating ribonucleic acids and novel metabolites, associated with various disease features. Mentored trainees are exposed to the range of cell and molecular biology techniques including immunohistochemistry, cellular laser microdissection, and imaging 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.

See Above: Cover of prestigious journal issue illustrating a micro CT of genetically engineered mouse brain, with a brain riddled with hemorrhagic lesions, imaged by the Awad laboratory. Such model mice catalyze novel discoveries of mechanisms of vascular malformation development, and brain bleeding, and test the effect of novel therapies before their use in humans.

Clinical Translation: Developing Novel Diagnostics and Therapeutics

Intracranial hemorrhages account for approximately one sixth of all strokes, yet they result in disproportionately catastrophic outcome, 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), that have been associated with case mortality rates exceeding 50% in community based studies, and case disability rates exceeding 80 %.  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 using thrombolytic aspiration and drainage, which hold great promise to change the clinical management of these devastating strokes. Dr Awad was the lead surgical investigator in the largest Phase III trials in this disease (www.cleariii.com and www.mistietrial.com), and has generated groundbreaking discoveries about the extent of blood evacuation needed to achieve the procedural benefit, and other surgical nuances, as well as the role of inflammatory response in this disease.

See Above: Novel treatment of cerebral hemorrhage by image guided placement of catheter for clot aspiration and lysis. Studies by the Awad team have demonstrated the threshold of blood removal necessary to effect clinical benefit. This now guides the standard of surgical therapy in this disease.

Complementing the laboratory studies, novel imaging in human subjects has allowed characterization of permeability, perfusion and iron content on MRI as biomarkers of CCM disease activity. These have been developed as surrogate outcomes for Phase II trials, including currently NIH funded RhoKinase inhibition trial to prevent CCM rebleeding (AT CASH EPOC clinicaltrials.gov NCT02603328) and multisite trial readiness initiatives validating these biomarkers. A more recent research thrust has focused on developing blood tests using weighted combinations of key molecules identified in our laboratory, which help diagnose, monitor and even predict brain hemorrhage. Advanced statistical methods are being developed to optimize these novel smart blood tests. These tests are undergoing validations in funded NIH research, and are being developed for ultimate clinical use.

Awad oversees a team including a senior clinical research manager, a trial nurse, imaging scientists, statisticians and several predoctoral and postdoctoral trainees who oversee these clinical biomarker studies and trials.