Contribution of Vitamin D Deficiency to Pathological Progression in Models of Cerebral Hypoperfusion

摘要 维生素D缺乏(VDD)与许多非骨骼慢性疾病有关，包括 心血管疾病、中风、自身免疫性疾病和痴呆症，这些都是导致残疾和 世界范围内的死亡。VDD增加中风的风险和严重性，可能是因为维生素D调节血管内皮细胞 细胞功能、血管反应、先天免疫系统和适应性免疫系统。大量临床前研究 都专注于维生素D在急性中风中的作用，但尚不清楚VDD对中风的影响 慢性脑低灌注症的病理进展。慢性脑低灌注是一种普遍存在的 长期脑血流不足的状态，可导致脑白质损伤、神经炎症、 中风和认知障碍。在这里，我们建议使用两种慢性脑损伤的动物模型 低灌注率，结合维生素D修饰的饮食，以描述维生素D在病理中的作用 与脑血流量减少有关。双侧颈动脉狭窄(BCAS)是血管病变的一种模型。 痴呆症，与小血管疾病，血脑屏障(BBB)功能障碍，微梗塞， 和认知障碍。颈内动脉狭窄(ICAS)小鼠模型是作为 我的KL2项目专注于烟雾综合征，这是一种导致中风和 大脑底部的代偿性血管生成。ICAS模型与血管减少相关 血管内径增加、血管内皮生长因子(VEGF)增加、血脑屏障功能障碍和炎症。我们的 中心假设是VDD通过以下途径增加慢性脑低灌注的病理严重程度 血管功能障碍和慢性炎症增加，补充维生素D将减轻 这些影响。为了检验这些假设，我们提出了两个具体目标。目标1将重点放在低氧诱导 血管生成和血管壁病理，通过量化血管生成标记物、信号通路、血管 网络密度，以及评估血管壁的各种组件。目标2将专注于识别 炎性T细胞亚型(如Th17细胞)及其相关细胞因子和信号的定量 血液和脑组织中的路径。所有动物都将接受认知测试，以衡量其影响 维生素D修饰对慢性脑低灌注后功能结局的影响。总体而言，我们 我相信这项建议中进行的研究将解决几个关键的知识差距，利用集体 探讨维生素D在慢性脑低灌注症病理过程中的作用。 这项研究的结果将广泛适用于患有脑血流减少的患者，如 如动脉粥样硬化、烟雾综合征和血管性痴呆。利用维生素D的未来扩展研究 对于全世界的这些患者来说，干预代表着一种潜在的新的治疗方法。

ABSTRACT Vitamin D deficiency (VDD) is linked to a number of non-skeletal chronic conditions, including cardiovascular disease, stroke, autoimmune disease, and dementia, which are leading causes of disability and death worldwide. VDD increases the risk and severity of stroke, likely because vitamin D regulates endothelial cell function, vascular response, and the innate and adaptive immune system. Numerous preclinical studies have focused on the role of vitamin D in acute stroke, but what is not known are the effects of VDD on the pathological progression of chronic cerebral hypoperfusion. Chronic cerebral hypoperfusion is a pervasive state of long-term cerebral blood flow insufficiency that can lead to white matter damage, neuroinflammation, stroke, and cognitive impairment. Here, we propose to utilize two animal models of chronic cerebral hypoperfusion, in combination with a vitamin D modified diet, to delineate the role of vitamin D in pathologies associated with reduced cerebral blood flow. Bilateral Carotid Artery Stenosis (BCAS) is a model of vascular dementia, which is associated with small vessel disease, blood-brain barrier (BBB) dysfunction, micro-infarcts, and cognitive impairment. The Internal Carotid Artery Stenosis (ICAS) mouse model was developed as part of my KL2 project focused on moyamoya syndrome, a cerebrovascular condition that leads to stroke and compensatory angiogenesis at the base of the brain. The ICAS model is associated with decreased vessel diameter, increased vascular endothelial growth factor (VEGF), BBB dysfunction, and inflammation. Our central hypothesis is that VDD increases the pathological severity of chronic cerebral hypoperfusion, through increased vascular dysfunction and chronic inflammation, and that vitamin D supplementation will attenuate these effects. To test these hypotheses, we propose two specific aims. Aim 1 will focus on hypoxia-induced angiogenesis and vessel wall pathology, via quantification of angiogenic markers, signaling pathways, vascular network density, and assessment of the various components of the vessel wall. Aim 2 will focus on identifying inflammatory T cell subtypes (e.g., Th17 cells) and quantification of associated cytokines and signaling pathways in the blood and brain tissue. All animals will be subjected to cognitive testing to measure the effects of vitamin D modification on functional outcome following chronic cerebral hypoperfusion. Collectively, we believe the studies pursued in this proposal will address several critical knowledge gaps, utilizing a collective approach to define the role of vitamin D in the pathological progression of chronic cerebral hypoperfusion. Results from this study will be broadly applicable to patients suffering from reduced cerebral blood flow, such as atherosclerosis, moyamoya syndrome, and vascular dementia. Future expanded studies utilizing vitamin D intervention represent a potentially novel therapeutic for these patients worldwide.