Endothelial Cell Epigenetics and Blood-Brain Barrier.

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PROJECT SUMMARY/ABSTRACT: Several clinical trials targeting neuronal injury have failed to demonstrate significant benefit in stroke patients. Recent studies suggest that there is a significant vascular component to poor functional outcomes after stroke, particularly post-stroke blood-brain barrier (BBB) disruption. Currently no treatments available to treat leaky BBB and rejuvenate central nervous system (CNS) vessels after stroke. Here we propose two different approaches to reach this goal. Aim 1: Gene expression patterns are set, in part, by epigenetic processes that classify the genome into active and silent to support the development and differentiation. Nearly nothing is known about the epigenetic mechanisms that govern the development of BBB. This approach is based on the central premise that understanding the epigenetic mechanisms that regulate the formation of an intact BBB could identify novel targets to modulate BBB. Interestingly, in our preliminary experiment, we found that during development some important BBB genes are transcriptionally repressed in adult CNS endothelial cells (ECs-epicenter of BBB). Further, we discovered that the two major epigenetic enzymes histone deacetylate 2 (HDAC2) and polycomb repressive complex 2 (PRC2) mediate this transcriptional repression. Based on these novel findings, we propose that, during embryonic brain development, the epigenetic regulators HDAC2 and PRC2 establish an intact BBB via transcriptional repression of specific BBB genes. Further, we hypothesize that, while this expression profile is essential for maintaining a functional BBB in adults, it also contributes to impaired BBB repair by CNS ECs following stroke. This study will identify the epigenetic regulators HDAC2 and PRC2 as new therapeutic targets to manipulate BBB during disease and therapy and will advance current knowledge regarding BBB development. Aim 2: Our second approach is to target a core signaling pathway in cerebral vessels. During early brain development, the Wnt/β-catenin pathway orchestrates BBB development and CNS angiogenesis. However, the Wnt/β- catenin pathway diminishes during later vessel development and is almost inactive in adult CNS ECs, making it difficult to target this pathway for vascular repair in CNS diseases. Our new preliminary data demonstrate the epigenetic mechanism behind Wnt pathway inactivation in adult CNS ECs and show that the Wnt pathway can be re-activated in adult CNS ECs by epigenetic manipulation and Wnt ligand stimulation. Consequently, we hypothesize that reactivating the Wnt/β- catenin pathway in adult CNS ECs will restore the developmental phenotypes including BBB formation and angiogenesis in adult CNS ECs, thereby promoting BBB repair and vascular regeneration after stroke. The Wnt pathway, for a long time been said to be undruggable owing to its absence in adult vessels, our evaluations on targeting the Wnt pathway for BBB repair will shift the mindset, leading to targeting this pathway for CNS and other diseases. If successful this proposal will pave the way for the development of novel epigenetic and Wnt-targeting therapies to repair the BBB and improve outcomes in stroke patients. The overall impact of the project is high as it proposes a broadly applicable strategy to repair BBB which is central to several CNS disorders.