Acceleration of Circulatory and Neurological Aging due to Wildfire Exposures

野火暴露导致循环系统和神经系统老化加速

• 批准号: 10544543
• 负责人: Matthew J Campen
• 金额: $ 75.65万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10544543
• 关键词: Acceleration; Acute; Age; Aging; Alzheimer' s Disease; Amyloid; Amyloid beta-Protein; Animals; Anti-Inflammatory Agents; Astrocytes; Atherosclerosis; Attenuated; Blood; Blood - brain barrier anatomy; Blood Vessels; Brain; CD36 gene; Cardiovascular system; Cells; Chronic; Chronic Disease; Circulation; Complex; Complex Mixtures; Dementia; Disasters; Disease; Disease Marker; Elderly; Endothelial Cells; Endothelium; Environment; Environmental Exposure; Environmental Pollutants; Environmental Risk Factor; Etiology; Event; Exposure to; Gases; Genetic; Health; Histopathology; Human; Impairment; Inflammation; Inflammatory; Inhalation; Laboratories; Life; Ligands; Longevity; Lung; Matrix Metalloproteinases; Mediator; Metabolic; Metabolism; Metalloproteases; Microglia; Molecular; Neurologic; Neurological outcome; Outcome; Ozone; Particulate; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Peptide Fragments; Peptide Hydrolases; Peptides; Phenotype; Population; Predisposition; Process; Protein Fragment; Proteins; Proteome; Proteomics; Receptor Cell; Research; Resveratrol; Role; SIRT1 gene; Serpins; Serum; Smoke; Structure; System; Testing; Therapeutic Uses; Toxicology; United States; Up-Regulation; Vascular Cell Adhesion Molecule-1; Vascular Diseases; Vascular Endothelial Cell; Wildfire; age related; biomass fuel; cerebrovascular; environmental stressor; experience; extreme weather; glial activation; healthspan; improved; in vivo; lung injury; mouse model; multiple omics; neural; neuroinflammation; neurological pathology; neuropathology; pathological aging; pharmacologic; pollutant; receptor; recruit; response; secretory protein; senescence; tau Proteins; therapeutic target; toxicant; wood smoke

SUMMARY: Acceleration of Circulatory and Neurological Aging due to Wildfire Exposures Wildfires pose an increasing threat to a growing and aging global population, notably in the Western United States. Little is known about the influence of inhaled environmental pollutants, such as from wildfire smoke (WFS) exposure, on molecular pathways governing cerebrovascular and neurological aging in the etiology of Alzheimer’s disease (AD) and dementia. Yet, parallel molecular changes are induced by aging and inhaled toxicants within the blood, raising the potential for their negative interaction. This includes increased metalloproteinases, serpins and inflammatory factors that can directly promote age-related neurological pathologies. Moreover, our research documents how inhaled pollutants cause blood compositional changes, particularly as protease-induced peptides, that promote vascular dysfunction and neurological inflammation. Inhaled toxicant induced circulating factors promote blood-brain barrier (BBB) permeation, glial activation and pro-inflammatory secretion and recruitment, and elevation of AD markers such as amyloid beta. Inhaled toxicant and age-related BBB deficits and associated sequelae show common involvement for vascular cell adhesion molecule-1 (VCAM-1), which is directly increased on cerebrovascular endothelial cells following exposure to WFS. Thus, we hypothesize that WFS augments pathological aging outcomes of senescence- associated secretory proteins in the circulating milieu to advance BBB compromise, neuroinflammation, and prime AD pathogenesis principally through expression/activity of cerebrovascular VCAM-1. To test this hypothesis, our team proposes the following aims: 1. Assess interaction between WFS exposure-induced and aging-related circulatory changes as drivers of BBB impairment, neuroinflammation, and early evidence of amyloid and tau proteinopathy. Serum compositional changes caused by aging x WFS exposure will be comprehensively assessed at the protein, peptide and metabolite levels and paired with in vivo histopathology and functional ex vivo phenotyping of major hallmarks of neurological and cardiovascular aging. 2. Delineate the role of cerebrovascular endothelial receptors, namely CD36, as intermediates in WFS-induced neuroinflammation. CD36 is clearly involved in acute responses of the BBB to inhaled toxicants, and likely to upregulation of VCAM-1, which has been recently implicated as a mediator of aging-related neurological sequelae. 3. Pharmacologically attenuate accelerated aging from WFS exposure using a sirtuin-1 activator (resveratrol) with an NAD+ booster (NMN) and/or a senolytic cocktail to reduce aging-related circulating factors. These permutations will target the key outcomes of circulatory changes from WFS exposure in target cells (vascular, neural) to reduce early pro-AD pathogenic BBB compromise, neuroinflammation and proteinopathy related outcomes. Together, findings will detail the influence of WFS in advancing age-related AD pathogenesis by generating vascular-compromising and glial-stimulating factors in the circulation, and evaluate counteracting therapeutics for use following unavoidable WFS exposure.

摘要：野火暴露导致循环系统和神经系统老化加速 野火对不断增长和老龄化的全球人口构成越来越大的威胁，特别是在美国西部地区 人们对吸入环境污染物（例如野火烟雾）的影响知之甚少。 （WFS）暴露，在病因学中控制脑血管和神经衰老的分子途径 然而，衰老和吸入也会引起类似的分子变化。 血液中的有毒物质，增加了它们负面相互作用的可能性。 金属蛋白酶、丝氨酸蛋白酶抑制剂和炎症因子可直接促进与年龄相关的神经功能 此外，我们的研究记录了吸入污染物如何导致血液成分变化， 特别是作为蛋白酶诱导的肽，可促进血管功能障碍和神经炎症。 吸入毒物诱导的循环因子促进血脑屏障（BBB）渗透、神经胶质活化和 促炎性分泌和募集，以及 AD 标志物（如β淀粉样蛋白）的升高。 有毒物质和与年龄相关的血脑屏障缺陷和相关后遗症显示血管细胞普遍受累 粘附分子-1 (VCAM-1)，在脑血管内皮细胞上直接增加 因此，我们发现 WFS 会增强衰老的病理性衰老结果。 循环环境中相关的分泌蛋白可促进 BBB 损害、神经炎症和 主要通过脑血管 VCAM-1 的表达/活性来确定 AD 发病机制。 根据假设，我们的团队提出以下目标： 1. 评估 WFS 暴露引起的和 与衰老相关的循环变化是 BBB 损伤、神经炎症和早期证据的驱动因素 淀粉样蛋白和 tau 蛋白病由衰老 x WFS 暴露引起。 在蛋白质、肽和代谢物水平上进行全面评估，并与体内组织病理学相结合 2. 描述神经和心血管衰老的主要特征的功能性离体表型。 脑血管内皮受体（即 CD36）作为 WFS 诱导的中间体的作用 CD36 显然与 BBB 对吸入毒物的急性反应有关。 VCAM-1 的上调，最近被认为是与衰老相关的神经系统的介质 3. 使用 Sirtuin-1 激活剂从药理学上缓解 WFS 暴露引起的加速衰老。 （白藜芦醇）与 NAD+ 增强剂 (NMN) 和/或 senolytic 鸡尾酒一起减少与衰老相关的循环 这些排列将针对目标中 WFS 暴露引起的循环变化的主要结果。 细胞（血管、神经），以减少早期 AD 致病性 BBB 损害、神经炎症和 总之，研究结果将详细说明 WFS 对促进年龄相关的影响。 AD 的发病机制是通过在循环中产生血管受损因子和神经胶质刺激因子，以及 评估在不可避免的 WFS 暴露后使用的抵消疗法。