Relative to blood vessels in the rest of the body, the blood vessels in the brain have specialized functions that make them very selective with respect to what substances they permit to transfer between the bloodstream and the brain. This function is commonly referred to as the blood-brain barrier (BBB) and may become compromised in various brain diseases, but the reason for this change is often unclear. The goal of this Faculty Early Career Development Program (CAREER) award is to investigate the hypothesis that changes in the stiffness of the extracellular matrix of blood vessels are one of the causes of dysfunction of the blood-brain barrier. This research will be accomplished by conducting measurements directly on blood vessels dissected from mouse and human brain tissue as well as by building blood vessel models from human stem cells through which the matrix stiffness and other parameters can be precisely controlled. These results will provide key insight into fundamental processes related to the progression of changes in brain vascular physiology due to aging or disease. In conjunction with this research plan, new educational and outreach activities will be developed and disseminated. In collaboration with a local artist and high school students who will perform research in the PI?s lab, a series of educational materials will be developed to explain how stem cells can be used for understanding and treating diseases. These materials will be disseminated at a Nashville science outreach center, through after-school clubs for economically disadvantaged students, and a yearly neuroscience event, thus promoting learning and engagement in the local community.
The overall research goal of this award is to understand the mechanobiology of the blood-brain barrier, specifically related to the interaction of the cerebrovascular mechanics with BBB function. This will be accomplished through two primary research objectives. The first objective is to fundamentally characterize how neurovascular tissue stiffness influences blood-brain barrier function in situ (in natural tissue) and in vitro (in engineered tissue). The in situ portion of the project will characterize the neurovascular stiffness, blood-brain barrier leakage, and extracellular matrix remodeling as a function of age and disease using mouse and human brain tissue samples. The in vitro portion of the work will develop blood-brain barrier mimics using induced pluripotent stem cells that can model this structure. These mimics will then be used to directly examine the effect of substrate stiffness on blood-brain barrier function. The second objective is to elucidate the biophysical mechanisms, specifically the mechanical triggers and the molecular signals, that regulate neurovascular stiffening in 2D and 3D culture. The focus will be on both autonomous and cross-talk signaling for the various cells that make up the blood-brain barrier. Understanding more fully the blood-brain barrier -- and in particular how changes in vascular stiffness that occur during aging and other pathologies may impact its function -- is a key area for understanding cerebrovascular physiology and how materials can be transported (or prevented from being transported) to the brain tissue.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
