Targeting Kruppel-like Transcription Factor for White and Grey Matter Protection in Vascular Cognitive Impairment and Dementia

血管性认知损害和痴呆(VCID)是一种主要由以下因素引起的认知障碍 脑血管病变和功能障碍，被广泛认为是第二大常见原因 阿尔茨海默病后的痴呆，给我们的社会造成了巨大的经济和社会负担。 尽管VCID的研究最近取得了进展，但我们对脑血管对 VCID的发病机制仍然有限，目前尚无有效的治疗方法。 KRüppel样因子是锌指转录因子家族的成员，由18个成员组成 已被证明在细胞生长和分化中发挥关键作用的成员。累积研究 已经记录了几个KLF(KLF2、KLF4、KLF5、KLF6、KLF8、KLF11、KLF13、KLF14和KLF15) 与发育和病理血管过程有关。越来越明显的是，KLF也 提示其对脑血管疾病的发病机制有调节作用，值得进一步研究。KLF11 是18个KLF家族成员中唯一的糖尿病相关KLF转录因子，具有高度的 在血管内皮细胞中表达。我们首次报道了KLF11作为一种重要的 急性卒中致脑损伤的中介物。然而，KLF11在调控中的功能和机制 VCID患者的脑血管发病机制和认知功能减退的进展完全未知。 在我们最近的初步研究中，我们发现KLF11的表达在 VCID后的小鼠脑血管构筑。值得注意的是，EC选择性的KLF11转基因过表达 减少实验性VCID小鼠模型的认知障碍，而KLF11基因缺陷 导致认知障碍增加，脑白质损伤和神经元丢失。从机械上讲，我们有 证明KLF11基因缺陷增加了VCID后小鼠的血脑屏障通透性。我们进一步发现 主要内皮紧密连接启动子区域的几个KLF11结合位点，以及基因缺失 在VCID小鼠中，KLF11显著降低了脑中claudin-5的表达。这些发现为我们提供了 我们的中心假设的基础是，血管KLF11可以减轻血脑屏障的破坏和随后的 慢性脑低灌注后的病理级联，从而导致血脑屏障的增加 在VCID患者中，稳定、减少白质/神经元丢失，并改善长期认知结果。 这项提案将实现三个具体目标。目的1：明确血管KLF11在长期中的作用 实验性VCID的认知障碍、脑白质损伤和神经元丢失；目标2：阐明 血管KLF11介导的脑保护机制在VCID中的作用目的3：探索TAT-TAT的系统递送 KLF11蛋白在VCID治疗中的应用阐明KLF11脑血管保护可能有助于我们 发现血管对脑白质和灰质损伤和痴呆的贡献，并引导我们开发新的 以及对VCID的有效治疗。

Vascular cognitive impairment and dementia (VCID), a type of cognitive disorder mainly induced by cerebrovascular pathology and dysfunction, is widely recognized as the second most common cause of dementia after Alzheimer’s disease, and results in tremendous economic and social burdens on our society. Despite recent progress in VCID research, our understanding of cerebrovascular contributions to the pathogenesis of VCID is still limited, and the effective therapeutic approaches for VCID are unavailable. Krüppel-like factors (KLFs) are members of the zinc finger family of transcription factors and consist of 18 members that have been shown to play key roles in cellular growth and differentiation. Cumulative studies have documented that several KLFs (KLF2, KLF4, KLF5, KLF6, KLF8, KLF11, KLF13, KLF14, and KLF15) are implicated in developmental and pathological vascular processes. It is becoming apparent that KLFs are also implicated in regulating the pathogenesis of cerebrovascular diseases and warrant further investigation. KLF11 is a unique diabetes-associated KLF transcription factor among 18 KLF family members and is highly expressed in vascular endothelium. We reported for the first time that KLF11 functions as an important mediator in acute stroke-induced brain injury. However, the function and mechanisms of KLF11 in regulating cerebrovascular pathogenesis and progression of cognitive decline are totally unknown in VCID. In our recent preliminary studies, we have shown that KLF11 expression is significantly decreased in the mouse cerebral vasculature after VCID. Of note, EC-selective KLF11 transgenic overexpression displays reduced cognitive impairments in the experimental VCID mouse model, whereas KLF11 genetic deficiency results in increased cognitive impairments, white matter injury and neuronal loss. Mechanistically, we have documented that KLF11 genetic deficiency increased BBB permeability in mice after VCID. We further found several KLF11 binding sites in the promoter region of major endothelial tight junctions, and genetic deletion of KLF11 in VCID mice significantly reduced cerebral expression of claudin-5. These findings have provided the basis for our Central Hypothesis that vascular KLF11 attenuates BBB disruption and subsequent pathological cascades after chronic cerebral hypoperfusion, thereby contributing to increased BBB stabilization, reduced white matter/neuronal loss, and improved long-term cognitive outcomes in VCID. Three specific aims will be performed in this proposal. Aim 1: Define the role of vascular KLF11 in long-term cognitive disorders, brain white matter injury, and neuronal loss in experimental VCID; Aim 2: Elucidate the mechanisms of vascular KLF11-mediated brain protection in VCID; Aim 3: Explore systematic delivery of TAT- KLF11 protein as a potential therapy in VCID. Elucidating KLF11 cerebrovascular protection may help us to discover vascular contribution to brain white and grey matter injury and dementia, and lead us to develop novel and effective treatment against VCID.