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

血管性认知功能障碍和痴呆（VCID）是一种主要由 脑血管病变和功能障碍，被广泛认为是第二个最常见的原因， 阿尔茨海默氏病之后的痴呆，并对我们的社会造成巨大的经济和社会负担。 尽管最近在VCID研究方面取得了进展，但我们对脑血管对VCID的贡献的理解仍然不足。 VCID的发病机制尚不清楚，目前尚无有效的治疗方法。 Krüppel样因子（KLF）是锌指转录因子家族的成员，由18个转录因子组成。 已显示在细胞生长和分化中发挥关键作用的成员。累积研究 已经证明了几个KLF（KLF 2、KLF 4、KLF 5、KLF 6、KLF 8、KLF 11、KLF 13、KLF 14和KLF 15） 与发育和病理性血管过程有关。很明显，KLF也是 参与调节脑血管疾病的发病机制，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， 在血管内皮中表达。我们首次报道了KLF 11作为一种重要的 急性脑卒中诱导的脑损伤中的介质。然而，KLF 11在调节细胞凋亡中的功能和机制尚不清楚。 在VCID中，脑血管发病机制和认知下降的进展是完全未知的。 在我们最近的初步研究中，我们已经表明，KLF 11的表达显着降低， VCID后的小鼠脑血管。值得注意的是，EC选择性KLF 11转基因过表达显示， 减少实验性VCID小鼠模型中的认知障碍，而KLF 11遗传缺陷 导致认知障碍、白色物质损伤和神经元损失增加。机械地说，我们有 证明KLF 11基因缺陷增加了VCID后小鼠的BBB通透性。我们进一步发现 主要内皮细胞紧密连接启动子区的几个KLF 11结合位点， VCID小鼠中的KLF 11显著降低了大脑中claudin-5的表达。这些发现提供了 我们的中心假设的基础，即血管KLF 11减弱BBB破坏和随后的 慢性脑灌注不足后的病理级联反应，从而导致BBB增加 稳定，减少白色物质/神经元损失，并改善VCID的长期认知结果。 本提案将实现三个具体目标。目的1：确定血管KLF 11在长期 实验性VCID中的认知障碍、脑白色物质损伤和神经元损失;目的2：阐明 血管KLF 11介导的VCID脑保护机制;目的3：探索达特的系统性递送- KLF 11蛋白作为VCID的潜在治疗。阐明KLF 11的脑血管保护作用可能有助于我们 发现血管对脑白色和灰质损伤和痴呆的贡献，并引导我们开发新的 有效治疗VCID。

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.