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）：牙龈卟啉单胞菌（Pg）不仅是牙周炎的病原体，而且还是多种口外感染的病原体，并且与动脉粥样硬化（ACD）的起始和/或进展有关。心血管内皮细胞是 是 ACD 等心血管疾病 (CVD) 发生和进展的关键。 Pg可以侵入各种类型的内皮细胞并导致这些细胞功能障碍，导致内皮细胞产生类似于人类ACD中发生的反应，特别是通过先天免疫途径刺激多个效应器。毫无疑问，炎症和自噬都会导致 ACD。 Pg 对 ACD 中经典炎症途径的刺激已得到充分研究。然而，Pg 介导的内皮自噬破坏对内皮功能障碍/ACD 的贡献和机制尚未阐明。我们小组最近的工作表明，Pg 对自噬途径的高度控制是促进内皮功能障碍的重要机制，从而导致促炎症反应、氧化应激增加和/或程序性细胞死亡。这导致宿主细胞无法充分应对压力，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血症应激期间利用自噬作为恢复稳态的手段的能力，导致内皮功能障碍，最终导致 ACD。本申请的目的是采用体外和体内方法来研究这一假设。我们建议比较能够篡夺自噬的 Pg 菌株和不能篡夺自噬的同基因突变体对内皮细胞功能障碍和 ACD 程度的影响，无论这种机制是否独立于先天免疫信号触发的促炎反应而发生，并确定打开或关闭自噬的药物是否可以将宿主细胞从 Pg 诱导的功能障碍中拯救出来。鉴于 ACD 和牙周炎内皮功能障碍的相似性，我们预计这些研究的许多结果也与内皮细胞和口腔疾病有关。