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: 8863982
• 负责人: Ann Progulske-Fox
• 金额: $ 49.11万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8863982
• 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; Environment; Etiology; Functional disorder; 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; Periodontal Diseases; 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; public health relevance; 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（由应用提供）：牙龈疟原虫（PG）不仅是牙周炎的病原体，而且还是各种口腔感染的病因学药，并且在动脉粥样硬化（ACD）的主动性和/或进展中隐含。心血管内皮细胞是 心血管疾病（CVD）（例如ACD）的主动性和进展的关键。 PG可以侵入各种类型的内皮细胞，并引起这些细胞功能障碍，从而导致内皮细胞的反应，与人类ACD中已知的相似，尤其是通过先天免疫途径刺激多种影响。毫无疑问，炎症和自噬都会导致ACD。对ACD中经典炎症途径的PG刺激已得到充分研究。但是，尚未阐明PG介导的内皮自噬对内皮自噬的破坏/ACD的贡献和机制。我们小组的最新工作表明，PG对自噬途径的高外套是一种重要的机制，可促进内皮功能障碍，从而导致促炎反应，增加氧化应激和/或程序性细胞死亡。这导致宿主细胞无法充分响应压力，从而导致细胞死亡。我们假设PG操纵内皮自噬的机制破坏了内皮细胞在氧化或高脂症状上使用自噬作为恢复体内稳态的手段的能力，从而导致内皮功能障碍，并最终，最终，ACD。该应用的目的是在体外和体内方法进行研究以研究这一假设。 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.鉴于ACD和牙周炎中内皮功能障碍的相似性，我们希望这些研究的许多结果也将与内皮细胞和口腔疾病有关。