Professor of Neurosurgery
Chair, Department of Neurosurgery
Professor in Neurology
Professor in Pediatrics
Professor in Neurobiology
Faculty Network Member of the Duke Institute for Brain Sciences
Member of the Duke Cancer Institute
Overview
The Grant Lab is a translational laboratory within the Preston Robert Tisch Brain Tumor Center at Duke, focusing on preclinical models using brain tumor xenografts to improve drug delivery of targeted agents across the blood-brain barrier.
Glioblastoma is a common, aggressive type of primary brain tumor associated with poor survival. Resection of brain tumors is followed by chemotherapy and radiation to ablate remaining malignant cell populations. Targeting these populations stands to reduce tumor recurrence and offer the promise of more complete therapy. Thus, improving access to the tumor, while leaving normal brain tissue unscathed, is a critical pursuit. A central challenge in this endeavor lies in the limited delivery of therapeutics to the tumor itself. The blood-brain barrier (BBB) is responsible for much of this difficulty but also provides an essential separation from systemic circulation. Due to the BBB's physical and chemical constraints, many current therapies, from cytotoxic drugs to antibody-based proteins, cannot gain access to the tumor.
Although we employ a multitude of both in vitro and in vivo techniques to study these barriers, we focus on in vivo multi-photon microscopy imaging which provides cellular resolution to study these changes in a temporal and quantitative fashion. We have a cranial window model coupled to a 2-photon microscope and closely track the tumor growing over time in an orthotopic tumor model in mice.
Publications
Personnel
Faculty Collaborators
Assistant Professor of Neurosurgery
Duke University
Dept. of Neurosurgery
Stanford University
Dept. of Neurosurgery
Stanford University
Lab Staff
Joan Wilson
Laboratory Research Analyst I
Lab Manager
Angela Everhart
Research Technician III
Collaborations
Projects in Collaboration with the lab of Wonjae Lee at Duke
Brain tumor model for immunotherapy
Brain tumors are associated with poor prognosis due to the limitations of conventional surgical and radiotherapeutic management in completely removing cancer-infiltrated tissues without affecting normal brain functions. Immunotherapy could be effective to treat tumors in the brain because it is less reliant on blood-brain barrier (BBB) permeability and relatively specific to cancer cells while preserving the brain tissue. However, brain tumors traditionally have been excluded from immunotherapy because brain tumor cells, benefiting from the unique immunologic features of the brain, establish immunosuppressive tumor environment and evade immune-mediated destruction. Our brain tumor model is used to identify biomarkers of immune evasion of brain tumors and develop biomarker-specific immunotherapy.
Ischemic stroke model for stem cell therapy
Stem cell therapy is currently spotlighted as a promising treatment option for stroke patients. However, the mechanism and critical factors responsible for its clinical efficacy have hardly been unveiled, making it very challenging to systemize the cell therapy administration for stroke patients. When stem/progenitor cells are injected through intravascular routes, as in most of the clinical trials, its efficacy is inevitably and critically dependent on the responses of the neurovascular units (NVU) to these extraneous cells. We are developing an engineered brain model with the microenvironment of ischemic stroke, recapitulating the natural interaction between the extraneous stem/progenitor cells and the host cells of NVU during post-stroke neuroregeneration. Our system would serve as a time- and cost-efficient test bed for identifying and testing the critical factors determining the clinical efficacy of stem cell therapeutics.
Understanding organ specificity of cancer metastasis
Each type of the cancer cells has its own organ preference for metastasis. Vasculature plays pivotal roles for the cancer cells to break away from where they first formed (primary cancer), to travel through the circulation system, and to form new tumors (metastatic tumors) in other organs. We are developing microfluidic metastatic models in which this organ specificity of cancer metastasis is simulated. Using these models we aim to elucidate the role of the vasculature in mediating the cross-communication between cancer cells and specific organ microenvironments. We expect that the identification of tissue-specific signals involved in this metastatic progression will lead to novel therapeutic strategies.
Understanding the role of the cerebral vasculature in Alzheimer’s disease
The functional and structural integrity of the cerebral vasculature is critical to the maintenance of cognitive functions. The patients of early Alzheimer’s disease (AD) show the deduction of the cerebral blood flow, thought to lead to various neurological disorders. The formation of amyloid plaques within brain parenchyma is thought to contribute to the degradation of the neurons in the brain and the subsequent symptoms of AD. However, the same amyloid plaques form in the walls of the cerebral vasculature as well. We would like to reconstruct these complicated interactions in our microfluidic chips and delineate the crosstalk among neurons and cerebral endothelial cells as well as the role of blood flow in their communication. Because vascular abnormalities might play an important role in the initiation and aggravation of AD, we hope to find a vascular route that can reverse the process or at least delay the deposit of amyloid plaques.