MOLECULAR PROGRAMMING OF THE VASCULATURE IN DEVELOPMENT AND DISEASE Proper formation and function of the vasculature are crucial for health and survival, as the vasculature supplies all cells in the body. A dysfunctional vasculature causes myriad diseases, including stroke, arterial occlusive diseases, and vascular anomalies. Our long-term goal is to identify novel drug targets and inform rational therapeutic designs to treat vascular diseases. Our strategy is to understand genes crucial for angiogenesis (new vessel formation) in the normal and diseased states, concentrating on the Notch, ephrin-B2, and TGF-beta pathways. We employ cutting-edge mouse genetics to delete or express genes in a cell lineage-specific and temporally controllable fashion in vascular cells. We combine these molecular approaches with mouse models of diseases as well as live 5D two-photon imaging (3D + blood flow over time) to uncover both the molecular mechanisms and hemodynamic signals in development and disease progression. These preclinical animal studies are coupled with patient sample validations. Our lab members come from diverse fields, including biology, bioengineering, and medicine, creating a collaborative and exciting environment. We strive to advance multiple projects across disciplines. PROJECTS Molecular programming of blood vessels: Building on our study of the developing dorsal aorta and cardinal vein, the first major artery-vein (AV) pair to form in the body, our lab aims to identify molecular regulators that program arteries and veins in vital organs during development and aging. We examine the interplay between genetic AV programming and flow-induced patterning. Understanding AV programming in normal angiogenesis provides important insights into how the genetic pathways can be hijacked in various disease states. Stroke: We study two types of stroke, ischemic stroke and hemorrhagic stroke. Ischemic stroke occurs when arteries supplying the brain are blocked. Using a surgical model of ischemic stroke, we aim to identify technologies enabling better recover following arterial blockade. Hemorrhagic stroke, on the other hand, occurs when diseased blood vessels rupture. Brain arteriovenous malformations (AVMs), which are direct connections from arteries to veins, are one of the major causes of hemorrhagic stroke. We investigate AV programming in both AVM progression and regression. Arteriovenous malformations: AVMs can occur anywhere in the body and comprise a category of hard to treat vascular anomalies. Most AVMs are sporadic, thus limiting the understanding of their etiology. In contrast, hereditary AVMs, such as those found in hereditary hemorrhagic telangiectasia (HHT) patients, offer an excellent opportunity to study how AVMs form. HHTs are caused by mutations in genes of the TGF-beta superfamily. We are interested in the molecular mechanisms underlying HHT-mediated AVMs formation. Arterial occlusive diseases: Arterial occlusive diseases occur when the arteries in the body are blocked, causing insufficient blood flow to the tissues. Blockage of arteries in the brain causes stroke, in the heart causes myocardial infarction, and in the extremities causes peripheral arterial disease. Arteriogenesis, a process by which small dormant arteries around the blockage enlarge to form collateral circulation, holds promise to restore blood flow and rescue affected tissues. We investigate pro-arteriogenic molecular regulators to uncover potential therapeutic strategies to enhance the body’s natural defense against arterial occlusive disease.