Inflammation and delayed cognitive dysfunction after stroke

中风后炎症和迟发性认知功能障碍

• 批准号: 10621096
• 负责人: Kristian Paul Doyle
• 金额: $ 201.69万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-15 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621096
• 关键词: Ablation; Adult; Animal Model; Anti-Inflammatory Agents; Antibodies; Area; Atherosclerosis; Automobile Driving; Biochemistry; Blood Vessels; Bone Marrow; Brain; Brain region; CD36 gene; Cell membrane; Cell physiology; Cells; Cerebrovascular Disorders; Cholesterol; Chronic; Cicatrix; Cognition; Data; Dementia; Dose; Encephalomalacia; Enzymes; Excision; FDA approved; Female; Foam Cells; Foundations; Goals; Heart; Hematogenous; Hippocampus; Human; Immune; Impaired cognition; Individual; Infarction; Infiltration; Inflammasome; Inflammation; Inflammatory; Inflammatory Response; Injury; Ischemia; Knowledge; Lipids; Liver X Receptor; Macrophage; Mediating; Microglia; Modeling; Molecular; Mouse Strains; Mus; Myelin; Myelogenous; Myeloid Cells; Myocardial Infarction; Nerve Degeneration; Outcome; Pathway interactions; Persons; Phagocytes; Plasma; Process; Production; Publishing; Quality of life; Recommendation; Recovery; Research; Role; Signal Transduction; Stroke; Survivors; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Transplantation; Up-Regulation; aged; behavior measurement; brain tissue; chronic stroke; cognitive function; cytokine; experience; healing; hydroxypropyl-beta-cyclodextrin; improved; lipid metabolism; lipidomics; male; mouse model; neurotoxic; novel; oxidized low density lipoprotein; post stroke; post stroke cognitive impairment; post stroke dementia; prevent; protein expression; sensor; sex; single-cell RNA sequencing; solute; stroke model; stroke recovery; transcriptional reprogramming; vascular cognitive impairment and dementia

PROJECT SUMMARY Decades of research have shown a strong association between cerebrovascular disease, including stroke, and subsequent cognitive impairment and dementia. However, vascular contributions to cognitive impairment and dementia (VCID) are still unclear. We have shown that there is a chronic inflammatory response following stroke that intensifies post-stroke injury, and in animal models, causes delayed cognitive impairment. As such, the chronic inflammatory response to stroke is a potential VCID. We recently demonstrated that at the molecular level, the chronic inflammatory response to stroke strongly resembles that seen in atherosclerosis due to the presence of foam cells, cholesterol crystals, and very similar expression of specific cytokines and degradative enzymes. In that regard, it is known that overwhelmed lipid processing within myeloid cells is a driver of atherosclerosis, features of which are dysregulated lipid metabolism within macrophages and production of high concentrations of neurotoxic cytokines and degradative enzymes. Lipids are principal structural components of myelin and are therefore major constituents of the human brain. Consequently, our overarching hypothesis is that following stroke, infiltrating macrophages and resident microglia become overwhelmed by the sheer volume of cholesterol and other lipids derived from the breakdown of myelin and other cell membranes and, as a result, cause the chronic inflammatory response described above. We propose that the permeation of cytokines and degradative enzymes produced within the infarct into neighboring brain regions is the principal cause of the encephalomalacia, or “softening,” that occurs to the tissue that surrounds chronic stroke infarcts. Thus, treatments that help phagocytic cells process the large amounts of lipid debris generated by the breakdown of brain tissue may temper the chronic inflammatory response to stroke and protect the surrounding brain tissue, thereby promoting healthier healing of the brain and improving recovery. In cases where the infarct is located within or adjacent to a brain region important for cognition, such treatments may even prevent dementia. Therefore, the goals of this proposal are to identify the pro-inflammatory lipid species generated, and pathways triggered, by the break-down of the lipid component of the brain following stroke (Aim 1); define the individual roles of pro-inflammatory lipid sensors in driving the chronic inflammatory response to stroke (Aim 2); and optimize our lipid removal approach within the area of chronic inflammation to improve recovery and prevent delayed cognitive impairment (Aim 3).

项目摘要 数十年的研究表明，包括中风在内的脑血管疾病与 随后的认知障碍和痴呆。然而，血管对认知障碍的贡献， 痴呆症（VCID）仍不清楚。我们已经证明中风后有慢性炎症反应 在动物模型中，它会加重中风后的损伤，导致延迟的认知障碍。因此， 对中风的慢性炎症反应是潜在的VCID。我们最近证明，在分子水平上， 水平，中风的慢性炎症反应与动脉粥样硬化非常相似， 存在泡沫细胞、胆固醇结晶，以及特异性细胞因子和降解性细胞因子的非常相似的表达。 内切酶在这方面，已知髓样细胞内过度的脂质加工是骨髓细胞增殖的驱动因素。 动脉粥样硬化，其特征是巨噬细胞内脂质代谢失调和高脂血症的产生。 神经毒性细胞因子和降解酶的浓度。脂质是主要的结构成分， 髓磷脂，因此是人脑的主要成分。因此，我们的总体假设是 中风后，浸润的巨噬细胞和常驻的小胶质细胞被大量的 胆固醇和其他脂质来源于髓鞘和其他细胞膜的分解，因此， 引起上述慢性炎症反应。我们认为细胞因子的渗透和 在梗塞内产生的降解酶进入邻近的脑区域是脑梗塞的主要原因。 脑软化，或“软化”，发生在慢性中风梗塞周围的组织。因此，在本发明中， 帮助吞噬细胞处理大量脂质碎片的治疗方法， 脑组织可以缓和对中风的慢性炎症反应并保护周围的脑组织， 从而促进大脑更健康的愈合并改善恢复。在梗塞部位 在对认知重要的大脑区域内或附近，这种治疗甚至可以预防痴呆症。 因此，本提案的目标是确定产生的促炎脂质种类和途径 触发，由脑卒中后大脑脂质成分的分解（目标1）;定义个体 促炎脂质传感器在驱动中风慢性炎症反应中的作用（目标2）;以及 优化我们在慢性炎症区域内的脂质清除方法，以改善恢复并预防 迟发性认知障碍（Aim 3）。