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

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

血管性认知障碍和痴呆（VCID），一种主要由血管性认知障碍引起的认知障碍脑血管病理和功能障碍被广泛认为是第二常见的原因阿尔茨海默病之后的痴呆症，给我们的社会带来巨大的经济和社会负担。尽管 VCID 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，并且尚无有效的治疗方法。 Krüppel 样因子 (KLF) 是转录因子锌指家族的成员，由 18 已被证明在细胞生长和分化中发挥关键作用的成员。已记录了几个 KLF（KLF2、KLF4、KLF5、KLF6、KLF8、KLF11、KLF13、KLF14 和 KLF15）越来越明显的是，KLF 也与发育和病理性血管过程有关。参与调节脑血管疾病的发病机制，值得进一步研究。是 18 个 KLF 家族成员中唯一的与糖尿病相关的 KLF 转录因子，并且高度我们首次报道了KLF11在血管内皮中的重要作用。然而，KLF11在调节中的功能和机制。 VCID 的脑血管发病机制和认知能力下降的进展完全未知。在我们最近的初步研究中，我们发现 KLF11 表达在值得注意的是，VCID 后的小鼠脑血管系统显示 EC 选择性 KLF11 转基因过度表达。实验性 VCID 小鼠模型中的认知障碍减少，而 KLF11 遗传缺陷从机制上讲，我们发现认知障碍、白质损伤和神经损失增加。我们进一步发现，KLF11 遗传缺陷增加了小鼠 VCID 后的 BBB 通透性。主要内皮紧密连接的启动子区域有几个 KLF11 结合位点，并且基因缺失 VCID 小鼠中的 KLF11 显着降低了claudin-5的大脑表达。我们的中心假设的基础是血管 KLF11 减弱 BBB 破坏和随后的慢性脑灌注不足后发生病理级联反应，从而导致 BBB 增加稳定、减少白质/神经元损失并改善 VCID 的长期认知结果。该提案将实现三个具体目标目标 1：明确血管 KLF11 的长期作用。实验性 VCID 中的认知障碍、脑白质损伤和神经元损失；目标 2：阐明 VCID 中血管 KLF11 介导的脑保护机制；目标 3：探索 TAT- 的系统递送； KLF11 蛋白作为 VCID 的潜在疗法阐明 KLF11 脑血管保护作用可能有助于我们发现血管对大脑白质和灰质损伤以及痴呆症的影响，并引导我们开发新的以及针对 VCID 的有效治疗。