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

• 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
• 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' 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

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.

摘要 维生素D缺乏症（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，这些疾病是残疾的主要原因， 全世界的死亡VDD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 已经集中在维生素D在急性中风中的作用，但不知道的是VDD对中风的影响。 慢性脑灌注不足的病理进展。慢性脑灌注不足是一种广泛的 长期脑血流不足状态，可导致白色物质损伤、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损伤的动物模型， 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）是一种血管狭窄模型， 痴呆，其与小血管疾病、血脑屏障（BBB）功能障碍、微梗塞， 和认知障碍。颈内动脉狭窄（ICAS）小鼠模型是作为以下研究的一部分开发的： 我的KL2项目集中在烟雾综合征，一种导致中风的脑血管疾病， 大脑底部的代偿性血管生成ICAS模型与血管减少有关 直径增加、血管内皮生长因子（VEGF）增加、BBB功能障碍和炎症。我们 中心假设是VDD增加慢性脑灌注不足的病理严重性， 增加血管功能障碍和慢性炎症，补充维生素D会减弱 这些影响。为了验证这些假设，我们提出了两个具体目标。目标1将重点关注缺氧诱导的 血管生成和血管壁病理学，通过定量血管生成标志物，信号通路，血管 网络密度和血管壁各种成分的评估。目标2将侧重于确定 炎性T细胞亚型（例如，Th17细胞）以及相关细胞因子和信号传导的定量 血液和脑组织中的通路。所有动物都将接受认知测试，以测量影响 维生素D修饰对慢性脑灌注不足后功能结果的影响。我们共同 我相信，本提案中所追求的研究将解决几个关键的知识差距，利用一个集体 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，如 如动脉粥样硬化、烟雾综合征和血管性痴呆。未来利用维生素D的扩展研究 干预代表了对全世界这些患者潜在新疗法。