Endothelial Metabolic Autophagy Mechanism of Vascular Dementia in Periodontopathic Infection

牙周病感染血管性痴呆的内皮代谢自噬机制

• 批准号: 10288951
• 负责人: OZLEM YILMAZ
• 金额: $ 34.48万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-10 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10288951
• 关键词: Address; Administrative Supplement; Adult; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease risk; American; Amyloid Fibrils; Amyloid beta-Protein; Autophagocytosis; Bacteria; Blood Vessels; Brain; Catabolism; Cells; Cellular biology; Characteristics; Chronic; Cognitive; Cognitive deficits; Consumption; Coupling; Data; Defect; Dementia; Development; Disease; Early Intervention; Endothelial Cells; Endothelium; Epithelial Cells; Equilibrium; Etiology; Experimental Models; Foundations; Functional disorder; Gingiva; Glutamate-Ammonia Ligase; Glutaminase; Glutamine; Glutathione Disulfide; Glycolysis; Goals; Human; Impaired cognition; Impairment; In Situ; In Vitro; Infection; Intervention; Invaded; Knowledge; Lead; Link; Measures; Mediating; Metabolic; Metabolic Pathway; Metabolism; Microbe; Microbiology; Molecular; Mucous Membrane; Mus; Nerve Degeneration; Neurocognitive; Neurodegenerative Disorders; Oral; Oxidation-Reduction; Oxidoreductase; Pathogenicity; Pathology; Pathway interactions; Patients; Periodontitis; Peroxidases; Phosphorylation; Pilot Projects; Populations at Risk; Porphyromonas gingivalis; Pre-Clinical Model; Presenile Alzheimer Dementia; Prevention; Public Health; Regulation; Research; Risk; Role; Sampling; Scientist; Tauopathies; Testing; Tissues; Vascular Cognitive Impairment; Vascular Dementia; Vascular Diseases; Visual; Work; aged; brain endothelial cell; brain metabolism; cellular pathology; cerebral microvasculature; chronic infection; cognitive development; comorbidity; critical period; glucose metabolism; microorganism; molecular marker; multiple chronic conditions; neurovascular; neurovascular unit; novel; oral infection; oxidation; parent grant; periodontopathogen; pre-clinical; small hairpin RNA; tau Proteins; translational research program; vascular cognitive impairment and dementia; vector

Recent research highlights the vascular contributions to cognitive impairment & dementia (VCID) as a leading factor of the cognitive disfunction identified in Alzheimer’s Disease and Related Dementias (AD/RD). In conjunction, growing evidence also underlines co-morbid pathology pointing to multifactorial disease etiology. Chronic periodontitis, which affects 47% of adults aged 30 years and older in the U.S. is lately associated with the increased risk of AD/RD and the major periodontal microorganism, Porphyromonas gingivalis has been proposed as an independent risk modifier in the AD field. Recent studies from our research group and others emphasize the potential systemic relocation of the live P. gingivalis from the gingival mucosa to the deeper tissue via intense microvasculature. Further, the bacterium was isolated in the AD patients’ brain samples, and several experimental models proposed P. gingivalis’ specific involvement in the hallmark cellular pathologies of AD/RD. However, significant knowledge gap still exists in the temporal development of AD/RD, since the hallmark molecular markers of the AD/RD are not sufficient by themselves to cause these disorders, while nearly half of the patients also manifest mixed features of VCID and AD pathologies. With this administrative supplement, we propose the novel central hypothesis that chronic infection by P. gingivalis targeting the neurovascular unit increases the pathogenicity of the VCID and leads to an earlier onset of the AD/RD. We specifically postulate that alteration of the brain endothelial glutamine metabolic pathways by P. gingivalis and its coupling to defective cellular autophagy via redox imbalance is an early pathophysiology in AD/RD. Thus, the immediate goal of this supplemental application is to initiate proof-of-concept preclinical models mechanistically addressing the emerging role of P. gingivalis to the development of neurovascular pathology and progressive cognitive decline that can be specifically targeted for prevention. This makes P. gingivalis an important topic of study, especially as the at-risk populations continue to age and grow larger. By merging our unique expertise in the cellular biology of P. gingivalis with Dr. Ergul, a clinician scientist and leader in the basic translational neurovascular pathobiology of cognitive decline /dementia, our long-term goal is to build a robust basic translational research program focusing on early intervention strategies against comorbid cognitive impairment /dementia in chronic periodontitis.

最近的研究强调了血管对认知障碍和痴呆（VCID）的贡献， 阿尔茨海默病和相关痴呆症（AD/RD）中认知功能障碍的主要因素。在 此外，越来越多的证据也强调指出多因素疾病病因的共病病理学。 慢性牙周炎影响美国47%的30岁及以上的成年人， AD/RD的风险增加和主要的牙周微生物牙龈卟啉单胞菌已经被 建议作为AD领域的独立风险修正因子。我们的研究小组和其他人最近的研究 强调活牙龈卟啉单胞菌从牙龈粘膜向更深处的潜在系统性重新定位 组织通过密集的微血管。此外，在AD患者的大脑样本中分离出细菌， 几个实验模型提出牙龈卟啉单胞菌特异性参与牙龈卟啉单胞菌的标志性细胞病理学， 助理署长/研发然而，在AD/RD的时间发展中仍然存在显著的知识差距，因为 AD/RD的标志性分子标志物本身不足以引起这些疾病， 几乎一半的患者还表现出VCID和AD病理的混合特征。与此行政 补充，我们提出了新的中心假设，慢性感染牙龈卟啉单胞菌针对 神经血管单位增加VCID的致病性，并导致AD/RD的早期发作。我们 特别假设牙龈卟啉单胞菌改变脑内皮谷氨酰胺代谢途径 并且其通过氧化还原失衡与有缺陷的细胞自噬的偶联是AD/RD的早期病理生理学。 因此，本补充申请的直接目标是启动概念验证临床前模型 从机制上解决牙龈卟啉单胞菌对神经血管病理学发展的新作用 和进行性认知能力下降，可以专门针对预防。这使得牙龈卟啉单胞菌成为 这是一个重要的研究课题，特别是随着高危人群继续老龄化和规模扩大。通过合并我们的 在牙龈卟啉单胞菌的细胞生物学独特的专业知识与Ergul博士，临床科学家和领导者， 认知衰退/痴呆的基本转化神经血管病理学，我们的长期目标是 建立一个强大的基础转化研究计划，重点是对共病的早期干预策略 慢性牙周炎中的认知障碍/痴呆。