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

维生素 D 缺乏对脑低灌注模型病理进展的影响

基本信息

批准号：
10725358
负责人：
Jill Marie Roberts
金额：
$ 15.3万
依托单位：
UNIVERSITY OF KENTUCKY
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：
2023-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10725358
关键词：
25-hydroxyvitamin D Adaptive Immune System Affect Age Alzheimer&apos s Disease Animal Model Animals Atherosclerosis Attenuated Autoimmune Diseases Awareness Bilateral Blood Blood - brain barrier anatomy Blood Vessels Blood brain barrier dysfunction Blood flow Cardiovascular Diseases Carotid Stenosis Cell physiology Cells Cerebrovascular Circulation Cerebrovascular Disorders Cerebrum Cessation of life Chronic Clinical Communities Data Dementia Development Diameter Diet Disease Endothelial Cells Exposure to External carotid artery structure Fat-Soluble Vitamin Female Food Future Hypoxia Impaired cognition Incidence Infarction Inflammation Inflammatory Ingestion Innate Immune System Internal Carotid Artery Stenosis Intervention Investigation Ischemia Ischemic Stroke Knowledge Link Maintenance Measures Microvascular Dysfunction Modeling Modification Moyamoya Disease Mus Neurodegenerative Disorders Pathologic Pathology Patients Production Public Health Regulation Research Research Design Risk Risk Factors Role Serum Severities Signal Pathway Signal Transduction Skin Stroke Stromal Cell-Derived Factor 1 Sunlight T-Lymphocyte Testing Therapeutic Vascular Dementia Vascular Diseases Vascular Endothelial Growth Factors Vasodilator Agents Vitamin D Vitamin D Deficiency Vitamin D supplementation absorption acute stroke angiogenesis attenuation brain based brain tissue cerebral hypoperfusion cerebrovascular cognitive testing cost cytokine density disability functional improvement functional outcomes male modifiable risk mouse model neuroinflammation novel therapeutic intervention novel therapeutics preclinical study response steroid hormone white matter white matter damage

项目摘要

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.

抽象的维生素 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，这些是导致残疾和残疾的主要原因全世界的死亡。 VDD 会增加中风的风险和严重程度，可能是因为维生素 D 调节内皮细胞细胞功能、血管反应以及先天性和适应性免疫系统。大量临床前研究重点关注维生素 D 在急性中风中的作用，但尚不清楚 VDD 对急性中风的影响慢性脑灌注不足的病理进展。慢性脑灌注不足是一种普遍现象长期脑血流不足的状态会导致白质损伤、神经炎症、中风和认知障碍。在这里，我们建议利用两种慢性脑病动物模型低灌注，结合维生素 D 改良饮食，以描述维生素 D 在病理学中的作用与脑血流量减少有关。双侧颈动脉狭窄（BCAS）是一种血管模型痴呆症，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 项目重点关注烟雾综合症，这是一种导致中风和大脑底部的代偿性血管生成。 ICAS 模型与血管减少有关直径、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 通过以下方式增加慢性脑灌注不足的病理严重程度：血管功能障碍和慢性炎症增加，补充维生素 D 会减弱这些影响。为了检验这些假设，我们提出了两个具体目标。目标 1 将重点关注缺氧引起的血管生成和血管壁病理学，通过量化血管生成标记物、信号传导途径、血管网络密度，以及血管壁各个组成部分的评估。目标 2 将侧重于识别炎症 T 细胞亚型（例如 Th17 细胞）以及相关细胞因子和信号传导的量化血液和脑组织中的通路。所有动物都将接受认知测试以衡量效果维生素 D 修饰对慢性脑灌注不足后功能结果的影响。总的来说，我们相信本提案中进行的研究将利用集体的方法来解决几个关键的知识差距确定维生素 D 在慢性脑灌注不足病理进展中的作用的方法。这项研究的结果将广泛适用于脑血流量减少的患者，例如如动脉粥样硬化、烟雾病综合征和血管性痴呆。未来利用维生素 D 进行的扩展研究干预为全世界这些患者提供了一种潜在的新型治疗方法。