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

针对血管认知障碍和痴呆症中白质和灰质保护的 Kruppel 样转录因子

• 批准号: 10625096
• 负责人: Kejie Yin
• 金额: $ 60.95万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10625096
• 关键词: Alzheimer' s Disease; Attenuated; Binding Sites; Blood - brain barrier anatomy; Blood Preservation; Blood Vessels; Brain; Brain Injuries; Cardiovascular system; Cells; Cerebrovascular Circulation; Cerebrovascular Disorders; Cerebrovascular Trauma; Cerebrovascular system; Cerebrum; Chronic; Cognition Disorders; Cognitive; Dementia; Development; Diabetes Mellitus; Differentiation and Growth; Diffuse; Economics; Endothelium; Extravasation; Family; Family member; Genetic; Immune; Impaired cognition; Inflammation; Inflammatory Response; Injury; Intravenous; Investigation; Kruppel-like transcription factors; Lesion; Mediating; Mediator; Molecular; Mus; Outcome; Pathogenesis; Pathologic; Peripheral; Permeability; Play; Process; Promoter Regions; Proteins; Regulation; Reporting; Research; Role; Societies; Tight Junctions; Time; Transactivation; Transgenic Organisms; Vascular Endothelium; Zinc Fingers; acute stroke; aged; blood-brain barrier disruption; blood-brain barrier permeabilization; brain endothelial cell; cell growth; cerebral hypoperfusion; cerebrovascular; cerebrovascular pathology; cognitive function; effective therapy; gray matter; hemodynamics; immune cell infiltrate; improved; member; migration; mouse model; neuron loss; novel; overexpression; preservation; prevent; social; therapeutically effective; transcription factor; transcription factor KLF13; vascular cognitive impairment and dementia; vascular contributions; white matter; white matter injury

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.

血管认知障碍和痴呆症（VCID），一种认知障碍，主要由 脑血管病理学和功能障碍，被广泛认为是第二个最常见的原因 阿尔茨海默氏病后的痴呆症，并在我们的社会上导致了巨大的经济和社会燃烧。 尽管VCID研究最近取得了进展，但我们对脑血管贡献的理解 VCID的发病机理仍然受到限制，VCID的有效治疗方法不可用。 Krüppel样因子（KLFS）是转录因子的锌指家族的成员，包括18个 已显示出在细胞生长和分化中起关键作用的成员。累积研究 已经记录了几个KLFS（KLF2，KLF4，KLF5，KLF6，KLF8，KLF11，KLF11，KLF13，KLF14和KLF15） 在发育和病理血管过程中实施。显然KLF也是 在调节脑血管疾病的发病机理中实施并需要进一步研究。 KLF11 是一个独特的糖尿病相关的KLF转录因子，在18 klf家族成员中，高度很高 在血管内皮中表达。我们首次报道KLF11起着重要的作用 急性中风引起的脑损伤的介体。但是，KLF11在调节中的功能和机制 在VCID中，脑血管发病机理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，我们表明KLF11表达显着降低 VCID后小鼠脑脉管系统。值得注意的是，EC选择性KLF11转基因过表达显示 实验VCID小鼠模型中的认知障碍减少了，而KLF11遗传缺乏症 导致认知障碍，白质损伤和神经元丧失增加。从机械上讲，我们有 证明KLF11遗传缺乏增加了VCID后小鼠的BBB渗透性。我们进一步发现 主要内皮紧密连接的启动子区域中的几个KLF11结合位点，以及遗传缺失的 VCID小鼠中的KLF11显着降低了Claudin-5的脑表达。这些发现提供了 我们的中心假设的基础，即血管KLF11减轻了BBB的破坏和随后的情况 慢性大脑灌注灌注后的病理级联反应，从而导致BBB增加 稳定，白质/神经元损失减少，并改善了VCID的长期认知结果。 该提案将执行三个具体目标。目标1：定义长期血管KLF11的作用 实验VCID的认知障碍，脑白质损伤和神经元丧失；目标2：阐明 VCID中血管KLF11介导的脑部保护的机制；目标3：探索系统的系统交付 KLF11蛋白作为VCID的潜在疗法。阐明KLF11脑血管保护可能有助于我们 发现对脑白质损伤和痴呆症的血管贡献，并导致我们发展新颖 和对VCID的有效治疗。