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.

最近的研究强调了对认知障碍和痴呆（VCID）的血管贡献 在阿尔茨海默氏病和相关痴呆症（AD/RD）中确定的认知失功能的主要因素。在 结合，越来越多的证据也强调了指向多因素疾病病因的合并病理学。 慢性牙周炎最近影响美国30岁及以上的成年人，最近与 AD/RD的风险增加和主要的牙周微生物，牙龈卟啉单胞菌一直是 在广告字段中提议为独立风险修饰符。我们的研究小组和其他研究的最新研究 强调活牙龈牙龈疟原虫从牙龈粘膜的潜在系统性搬迁到更深的 通过强烈的微脉管组织组织。此外，在AD患者的大脑样本中分离细菌，并 几个实验模型提出了牙龈疟原虫在标志性细胞病理学中的特异性参与 广告/路。但是，在AD/RD的临时发展中仍然存在着重要的知识差距，因为 AD/RD的标志性分子标记本身不足以引起这些疾病，而 几乎一半的患者还表现出VCID和AD病理的混合特征。使用此管理 补充，我们提出了一种新的中心假设，即牙龈疟原虫靶向慢性感染 神经血管单元增加了VCID的致病性，并导致AD/RD的早期发作。我们 特别假设牙龈疟原虫的脑内皮谷氨酰胺代谢途径改变 它通过氧化还原失衡与有缺陷的细胞自噬偶联是AD/RD的早期病理生理学。 这是此补充应用的直接目标是启动概念验证临床前模型 机械地解决牙龈疟原虫在神经血管病理发展中的新兴作用 以及可以专门针对预防的渐进认知下降。这使得牙龈疟原虫 重要的研究主题，尤其是随着处于危险人群的持续变化并增长更大的时候。通过合并我们的 与临床科学家和领导者Ergul博士的细胞生物学专业知识 认知能力下降 /痴呆的基本转化神经血管病理生物学，我们的长期目标是 建立一项强大的基本翻译研究计划，重点是针对合并的早期干预策略 慢性牙周炎的认知障碍 /痴呆症。