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.

Neurovascular Surgery Research Team

Issam Awad, MD, MSc, FACS, MA (Hon)

The John Harper Seeley Professor of Neurological Sciences

Professor of Neurological Surgery,

Neurology and the Committee on Neurobiology

Director of Neurovascular Surgery

Neurosurgeon scientist, principal investigator

Research Profile

Heba Ali

Heba Ali, PhD is a postdoctoral scholar in Dr. Awad's lab. Her focus interest is to understand and investigate the differential analysis of signals of the CCM genes and other linked structural changes in brain vasculature. Heba also probes into detecting plasma-based biomarkers to identify specific proteins, circulating microRNAs, and metabolites, associated with CCM and linked diseases

Dehua Bi

Dehua Bi is a third year PhD student in Biostatistics in the Public Health Science department. His role in the lab is to help with statistical analysis and to bring a Bayesian perspective with some potential new Bayesian methods to the data analysis team.

Chang Chen

Dr. Chang Chen is a bioinformatician working for Dr. Awad’s lab since 2020. Chang’s research mainly focuses on using machine learning and statistical modeling on different types of genome sequencing data to identify the biomarkers in complex neurovascular diseases, especially cerebral cavernous malformation (CCM).

DeBiasse

Dorothy DeBiasse

Dorothy DeBiasse is a Research Specialist in Dr. Awad’s lab, aiding in experimental analysis of proteome, metabolome, transcriptome of CCM patients in human and pre-clinical model of CCM disease. She conducts MRI imaging for study candidates as well as data acquisition.

Romuald Girard

Romuald Girard, PhD is a research assistant professor within the neurovascular research lab, working primarily on identifying novel circulating and imaging biomarkers of brain hemorrhagic activity. He’s focused on using advanced computational Machine Learning approach to develop mechanistically relevant biomarkers using multi-omic datasets.

Stephanie Hage

Stephanie Hage, MD, MSc is a Postdoctoral Research Fellow in Dr. Awad's lab. Her main work is on the Bayesian Adaptive Design in Phase IIA Biomarker Trial, a clinical trial funded by the NIH to assess the impact of therapy on multiple biomarkers of disease.

Justine Lee

Justine Lee, BSN, RN is a Clinical Research Nurse. She joined Dr. Awad’s lab after 5 years of bedside nursing, the majority in neurosurgical care and neurocritical care, as well as two years in case management. Justine works to oversee, facilitate, and participate in the conduct of two clinical trials, working alongside Dr. Awad and his research team focusing on cerebral cavernous malformations. With the senior project manager, they will coordinate and conduct two studies and assist with, plan, and implement the clinical study’s goals and objectives.

 

Ying Li

Ying Li, MS, MD is from Harbin Medical University, China. She joined Dr. Awad’s lab to complete her PhD. Ying’s research focus is to sort through cell populations in frozen CCM lesions, including endothelial cell, pericyte, microglia and astrocyte, for single-cell RNA sequencing and discover the potential DE genes that may reflect the cell non-autonomous effect.

Rhonda Lightle

Rhonda Lightle is the Lab Manager and Research Specialist III in Dr. Awad’s research lab.  Besides looking after the people, supplies and the lab space she is a histotechnologist who also does micro-CT acquisition, blood processing and helps the research fellows and students with experiments.

Thomas Moore

Thomas Moore is a Research Specialist III (histotechnologist) in Dr. Awad’s research lab. He specializes in histology and micro-CT for the phenotypic study of CCM mouse models. Thom oversees the workflow of the phenotyping core with external collaborators. Additionally, he crosses over into human clinical work with blood processing and biomarkers.

Daniel Nava

Daniel Nava is the Program Administrator for the Safadi Program of Excellence in Clinical and Translational Neuroscience. He serves as the liaison between clinical and research teams, and administrative support for the neurological surgery and HHT (hereditary hemorrhagic telangiectasia) sections. 

Sean Polster

Assistant Professor

Safadi Faculty Scholar

Neurosurgeon Scientist

The Polster laboratory is dedicated to understanding the basic mechanisms of endothelial dysfunction within the neurovascular unit (the interface of the body's blood vessels and the cells of the brain). Specifically, he focuses on mechanisms of inflammation, neurovascular dysfunction and the gut-brain-axis in radiation injury to the brain.

Research Profile

Sharbel G. Romanos

Sharbel G. Romanos is a medical student and part-time research specialist within Dr. Awad’s lab, working primarily on developing plasma and imaging biomarkers of CCM disease. He is particularly focused on elucidating mechanistic links of miRNA and protein biomarker candidates. Additionally, he has contributed to studies aimed at exploring hemorrhagic activity in the aging brain.

Robert Shenkar

Robert Shenkar, PhD is a Research Associate Professor. He analyzes lesion burden in murine models of cerebral cavernous malformation disease that have been treated or not treated with agents that may affect this burden. Within the lesions in brain sections from these mice, Robert has also been analyzing acute and chronic hemorrhage, and inflammation.

Abhinav Srinath

Abhinav Srinath is a third year MD/PhD student at the University of Chicago, Pritzker School of Medicine, completing his PhD in Dr. Awad’s lab. For the past few years, Abhi has gained experience in biomarker development, histology, mouse model analyses, and clinical trial development/implementation. For his PhD, Abhi will be looking at hemorrhage in the aging brain, studying mechanisms and biomarker development using circulating plasma molecules. 

Agnieszka Stadnik

Agnieszka Stadnik, MS, is the clinical research manager.  She provides administrative leadership, strategic planning, and operational management for clinical research operations.  She also screens and enrolls research subjects and tracks regulatory compliance for all ongoing studies.

Podcasts and Lectures

Listen to Dr. Issam Awad discuss CCM on Scientific Sense

Dr. Awad and Scientific Sense host Gill Eapen discuss comprehensive transcriptome analysis of cerebral cavernous malformation (CCM) across multiple species and genotypes, Common transcriptome, plasma molecules, and imaging signatures in the aging brain and a Mendelian neurovascular disease, cerebral cavernous malformation, and A Roadmap for Developing Plasma Diagnostic and Prognostic Biomarkers of Cerebral Cavernous Angioma With Symptomatic Hemorrhage (CASH).

Philosophy of Science in Relevance to Neurosurgery

Originally intended for the 27th Annual Opening Lecture at the Research Update in Neuroscience for Neurosurgeons (RUNN), Dr. Awad discusses the Philosophy of Science in Relevance to Neurosurgery. Recorded on January 12, 2022 as part of The University of Chicago Medicine's Kluver Virtual Grand Rounds Series.