P. gingivalis mediated disruption of autophagy in endothelial dysfunction

牙龈卟啉单胞菌介导内皮功能障碍中自噬的破坏

• 批准号: 8916212
• 负责人: Ann Progulske-Fox
• 金额: $ 48.57万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-19 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8916212
• 关键词: Address; Apolipoprotein E; Apoptosis; Arterial Fatty Streak; Atherosclerosis; Attenuated; Autophagocytosis; Bacteremia; Bacteria; Cardiovascular Diseases; Cardiovascular system; Cell Death; Cells; Cessation of life; Disease; Endothelial Cells; Etiology; Functional disorder; Health; Homeostasis; Hour; Human; Immune; In Vitro; Infection; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Injury; Invaded; Knock-out; Knockout Mice; Mediating; Mouth Diseases; Mus; Oral cavity; Oxidative Stress; Pathogenesis; Pathway interactions; Periodontitis; Pharmaceutical Preparations; Porphyromonas gingivalis; Process; Reporting; Role; Signal Transduction; Stress; Testing; Work; cell injury; comparative efficacy; design; efficacy testing; endothelial dysfunction; human disease; in vivo; innovation; macrophage; mouse model; mutant; novel; oral bacteria; pathogen; preclinical study; prevent; response; therapeutic target; trafficking

DESCRIPTION (provided by applicant): P. gingivalis (Pg) is not only a pathogen in periodontitis but is also an etiological agent of a variety of extraoral infections and is implicatd in the initiation and/or progression of atherosclerosis (ACD). Cardiovascular endothelial cells are key to the initiation and progression of cardiovascular diseases (CVDs) such as ACD. Pg can invade various types of endothelial cells and causes dysfunction of these cells, resulting in a response by the endothelial cells that is similar to that known to occur in human ACD, especially the stimulation of multiple effectors via the innate immune pathways. There is no question that both inflammation and autophagy contribute to ACD. Pg stimulation of the classic inflammatory pathways in ACD has been well investigated. However the contribution and mechanism of Pg mediated disruption of endothelial autophagy on endothelial dysfunction/ACD has not been elucidated. Recent work by our group suggests that high jacking of the autophagic pathway by Pg is an important mechanism that promotes endothelial dysfunction which results in pro-inflammatory responses, increased oxidative stress, and/or programmed cell death. This results in an inability of the host cells to adequately respond to stress, causing cell death. We hypothesize that the mechanism by which Pg manipulates endothelial autophagy disrupts the endothelial cell's ability to use autophagy as a means of restoring homeostasis during oxidative or hyperlipidemic stress, resulting in endothelial dysfunction and, ultimately, ACD. The objective of this application is to employ both in vitro and in vivo approaches to investigate this hypothesis. We propose to compare the effects of a Pg strain able to usurp autophagy and an isogenic mutant that cannot on endothelial cell dysfunction and extent of ACD, whether or not this mechanism occurs independently of proinflammatory responses triggered by innate immune signaling, and determine if drugs that turn on or off autophagy rescue the host cell from Pg induced dysfunction. Given the similarities of endothelial dysfunction in ACD and periodontitis, we expect that many of the results of these studies would also relate to endothelial cells and oral disease.

描述（由申请人提供）：牙龈卟啉卟啉菌（Pg）不仅是牙周炎的病原体，也是多种口腔外感染的病因，与动脉粥样硬化（ACD）的发生和/或进展有关。心血管内皮细胞