Kruppel-like factor 11 and ischemic stroke

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DESCRIPTION (provided by applicant): The blood brain barrier (BBB) is one of the primary targets of cerebral ischemic insults, and resultant BBB dysfunction is well-recognized as a major hallmark of ischemic stroke. As a major component of BBB, brain microvascular endothelial cells (BMECs), together with the tight junctions (TJs) between BMECs, play a dominant role in modulating BBB integrity and paracellular permeability. Extensive studies have shown that breakdown of BBB initiates a devastating cascade of events, contributing to cerebral inflammatory responses, vasogenic edema, hemorrhagic transformation, and eventual neuronal loss in cerebral ischemia. Thus, it is important to identify mechanisms by which loss of BBB integrity can be reduced during ischemic stroke. Kruppel-like factors (KLFs) are members of the zinc finger family of transcription factors and consist of 17 members that have been shown to play key roles in cellular growth and differentiation. Recent studies have documented that partial KLF family members (KLF2, KLF4, KLF5, KLF6, and KLF11) are implicated in developmental and pathological vascular processes. However, the function of the KLF family in the cerebral vasculature is largely unexplored. KLF11 is a member of the KLF family with high expression in vascular endothelium. Mutations or variations in KLF11 gene result in Maturity Onset Diabetes of the Young 7 (MODY7), and are closely associated with human type 2 diabetes mellitus, a major risk factor for stroke. Previously, we reported for the first time that peroxisome proliferatr-activated receptor g-mediated cerebral vascular protection during ischemic insults needs recruitment of KLF11 as its critical coactivator, suggesting KLF11 as a potential mediator in stroke pathologies. However, the functional significance and mechanisms of KLF11 itself as a novel diabetes mellitus-associated transcription factor in regulating cerebrovascular pathogenesis are totally unknown in ischemic stroke. In our preliminary studies, we have shown that KLF11 genetic deficiency leads to increased BBB permeability in mouse brain after middle cerebral artery occlusion as well as increased leukocyte-endothelial rolling and adhesion in the vascular wall. Moreover, we also demonstrated that gain-of-KLF11 function by adenovirus can inhibit BMEC death after oxygen glucose deprivation. Furthermore, we also found several KLF11 binding sites in the promoter region of selective endothelial tight junctions, and genetic deletion of KLF11 in mouse significantly reduced cerebral expression of Claudin 5 and ZO-1 mRNAs. These findings have provided the basis for our Central Hypothesis that KLF11 functions as a novel master regulator in BBB pathologies and attenuates brain injury after ischemic stroke. Three aims will be performed in this proposal. Aim 1: Define the role of KLF11 in BBB dysfunction and brain injury after ischemic stroke; Aim 2: Define the molecular mechanisms of KLF11 in regulating ischemia-induced BBB dysfunction; Aim 3: Define the therapeutic and transcriptional modulation of KLF11 activities in ischemic stroke.