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：野火暴露导致循环和神经系统老化加速