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: 10363056
• 负责人: Matthew J Campen
• 金额: $ 79.39万
• 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/10363056
• 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 Circulation; Blood Vessels; Brain; CD36 gene; Cardiovascular system; Cells; Cerebrovascular system; Chronic; Chronic Disease; Complex; Complex Mixtures; 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 of activation protein; Metabolic; Metabolism; Metalloproteases; Microglia; Molecular; Neurologic; Neurological outcome; Outcome; Ozone; Particulate; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Peptide Fragments; Peptide Hydrolases; Peptides; Pharmacology; Phenotype; Population; Predisposition; Process; Protein Fragment; Proteins; Proteome; Proteomics; Receptor Cell; Research; Resveratrol; Role; SIRT1 gene; Serpins; Serum; Smoke; Structure; 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; neuroinflammation; neurological pathology; neuropathology; pathological aging; pollutant; receptor; recruit; relating to nervous system; response; secretory protein; senescence; tau Proteins; therapeutic target; toxicant; weather-related disaster; 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：由于野火暴露而导致的循环和神经衰老的加速 野火对不断增长和衰老的全球人口构成日益威胁，尤其是在西部联合 国家。关于内部环境污染物的影响，例如野火烟雾，知之甚少 （WFS）暴露于脑血管和神经衰老的分子途径 阿尔茨海默氏病（AD）和痴呆症。然而，平行分子变化是通过衰老引起的，并遗传了 血液中的有毒物质，增加了其负相互作用的潜力。这包括增加 金属蛋白酶，丝氨酸蛋白酶和炎症因子可以直接促进与年龄相关的神经系统 病理。此外，我们的研究记录了遗传污染物如何引起血液复合材料的变化， 特别是作为蛋白质诱导的肽，促进血管功能障碍和神经系统炎症。 吸入毒物诱导的循环因子促进血脑屏障（BBB）渗透，神经胶质激活和 促炎性分泌和招募，以及淀粉样蛋白β等广告标记的升高。 有毒物质和与年龄相关的BBB定义和相关后遗症显示血管细胞的共同参与 粘附分子-1（VCAM-1），在脑血管内皮细胞上直接增加 暴露于WFS。这就是我们假设WFS增强了感应的病理衰老结果 循环环境中相关的秘密蛋白质，以推动BBB妥协，神经炎症和 主要AD发病机理主要通过脑血管VCAM-1的表达/活性。测试这个 假设，我们的团队提出以下目的：1。评估WFS暴露引起的相互作用和 与衰老相关的电路随着BBB损伤，神经炎症的驱动因素的变化和早期证据 淀粉样蛋白和tau蛋白质病。 X WFS暴露引起的血清成分变化将是 在蛋白质，胡椒和代谢物水平上进行全面评估，并与体内组织病理学配对 以及神经和心血管衰老主要标志的功能性表型。 2。描绘 脑血管内皮受体的作用，即CD36，如WFS诱导的中间体 神经炎症。 CD36显然参与了BBB对遗传毒物的急性反应，并且可能 VCAM-1的上调，该上调最近被视为与衰老相关的神经系统的介体 后遗症。 3。使用SIRTUIN-1激活剂从WFS暴露中衰减的药理学衰老的加速衰老 （白藜芦醇）用NAD+助推器（NMN）和/或塞洛克斯鸡尾酒，以减少与衰老有关的循环 因素。这些排列将针对目标中WFS暴露的电路变化的关键结果 细胞（血管，神经元），以减少早期促进促进致病性BBB妥协，神经炎症和 蛋白质疗法相关的结果。一起，发现将详细介绍WFS在推动与年龄有关的影响方面的影响 通过在循环中产生血管促进和神经胶质刺激因素，而AD发病机理，并 评估不可避免的WFS暴露后使用的抵消治疗。