Mouse model of post-infection atherosclerosis

感染后动脉粥样硬化小鼠模型

• 批准号: 10432265
• 负责人: Moises Arturo Huaman Joo
• 金额: $ 8.1万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10432265
• 关键词: Address; Affect; Animal Model; Antibiotic Therapy; Antibiotics; Atherosclerosis; Attenuated; Automobile Driving; BCG Live; Blood; CCL2 gene; Cessation of life; Clinical; Data; Development; Diabetes Mellitus; Disease; Epidemic; Exhibits; Flow Cytometry; Foundations; General Population; Genus Mycobacterium; Human; Immune; Infection; Inflammation; Inflammatory; Interleukin-1 beta; Interleukin-6; Intervention; Knock-out; Knowledge; Low Density Lipoprotein Receptor; Malignant Neoplasms; Measures; Modeling; Monoclonal Antibodies; Mus; Mycobacterium Infections; Mycobacterium bovis; Mycobacterium tuberculosis complex; Neurodegenerative Disorders; Persons; Pharmaceutical Preparations; Recovery; Research; Rifampin; Risk; Risk Factors; Survivors; TNF gene; Tissues; Translational Research; Tuberculosis; Work; attributable mortality; cardiovascular disorder risk; chronic infection; cytokine; experimental study; insight; isoniazid; monocyte; mortality; mouse model; mycobacterial; non-alcoholic fatty liver disease; novel; oxidized low density lipoprotein; peripheral blood; recruit; therapy design; tuberculosis treatment

PROJECT SUMMARY Atherosclerotic cardiovascular disease (ASCVD) is the number one cause of mortality worldwide, leading to approximately 18 million deaths each year. Besides traditional risk factors, emerging data implicate certain prevalent infections as important contributors of ASCVD risk. We have shown that a globally-prevalent infection such as tuberculosis (TB) carries a 2-fold increased risk of developing ASCVD. Furthermore, TB survivors have a 3-fold increased risk of long-term all-cause mortality compared to the general population, with most deaths attributable to ASCVD. A considerable gap in knowledge is that the mechanisms driving the increased ASCVD risk after recovery from TB and similar chronic infections are unknown. Studies aimed to fill this gap are expected to result in a positive impact in our ability to design interventions to mitigate ASCVD risk after recovery from TB and other chronic infections. We will leverage proof-of-concept mouse experiments conducted by our group which showed that mycobacterial infection enhances inflammation and atherosclerosis development to further establish and characterize a mouse model of post-infection atherosclerosis. Thus, in Aim 1 we will establish the progression of atherosclerosis in mice after mycobacterial-infection clearance with standard antibiotics. In Aim 2, we will profile the activation and function of monocytes post-infection and their contribution to atherosclerosis, as monocytes are key players in atherosclerosis development and our preliminary data indicate that they remain primed after infection clearance. Successful accomplishment of the proposed research will allow the development of an essential mouse model providing a foundation to study mechanisms of post-infection atherosclerosis. We will use the proposed model and findings to support an R01 application aimed at deciphering post-infection progression of atherosclerosis and underlying immune mechanisms. Our results will have a broad translational science impact by providing a model to investigate mechanisms of ASCVD risk and other inflammation-driven diseases among survivors of post-treated chronic infections.

项目总结 动脉粥样硬化性心血管疾病(ASCVD)是全球头号死亡原因，导致 每年约有1800万人死亡。除了传统的风险因素外，新兴数据还隐含着某些 流行感染是ASCVD风险的重要贡献者。我们已经证明了一种全球流行的 结核病(TB)等感染使罹患ASCVD的风险增加2倍。此外，结核病 与普通人群相比，幸存者长期全因死亡的风险增加了3倍 大多数死亡可归因于ASCVD。知识上的一个相当大的差距是，推动 从结核病和类似的慢性感染中康复后ASCVD风险增加是未知的。旨在填补 这一差距预计将对我们设计干预措施以降低ASCVD风险的能力产生积极影响 在从结核病和其他慢性感染中康复后。我们将利用概念验证小鼠实验 由我们小组进行的研究表明，分枝杆菌感染会加剧炎症和动脉粥样硬化 进一步建立和表征感染后动脉粥样硬化的小鼠模型。因此，在 目的1在分枝杆菌感染清除后，我们将建立小鼠动脉粥样硬化的进展。 标准的抗生素。在目标2中，我们将描述感染后单核细胞的激活和功能，以及它们的 对动脉粥样硬化的贡献，因为单核细胞是动脉粥样硬化发展和我们的 初步数据表明，在感染清除后，它们仍处于准备状态。成功完成了 拟议的研究将允许开发基本的小鼠模型，为研究提供基础 感染后动脉粥样硬化的机制。我们将使用建议的模型和调查结果来支持R01 旨在破译动脉粥样硬化和潜在免疫感染后进展的应用 机制。我们的结果将通过提供一个模型来研究，从而产生广泛的翻译科学影响 治疗后慢性阻塞性肺疾病幸存者中ASCVD风险和其他炎症驱动疾病的机制 感染。