Mouse model of post-infection atherosclerosis

感染后动脉粥样硬化小鼠模型

基本信息

批准号：
10593082
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
项目类别：
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/10593082
关键词：
Acceleration Address Affect Animal Model Antibiotic Therapy Antibiotics Antimycobacterial Agents Aorta Atherosclerosis Attenuated Automobile Driving BCG Live Blood CCL2 gene Cessation of life Clinical Data Development Diabetes Mellitus Dimensions Disease Epidemic Exhibits Flow Cytometry Foundations General Population Genus Mycobacterium Human Immune Infection Inflammation Inflammatory Interleukin-1 beta Interleukin-6 Intervention Knockout Mice 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 non-alcoholic fatty liver disease novel oxidized low density lipoprotein peripheral blood recruit therapy design tuberculosis treatment

项目摘要

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.

项目摘要动脉粥样硬化心血管疾病（ASCVD）是全球死亡率的第一名，导致每年约有1800万人死亡。除传统的风险因素外，新兴数据暗示了一定普遍感染是ASCVD风险的重要促进者。我们已经证明了全球占优势的诸如结核病（TB）之类的感染伴随着患ASCVD的风险增加了2倍。此外，TB 与普通人群相比，幸存者的长期全因死亡率风险增加了3倍，大多数归因于ASCVD的死亡。知识的一个很大的差距是，驱动的机制从结核病中恢复和类似慢性感染后，ASCVD风险增加尚不清楚。旨在填补的研究预计这一差距将对我们设计干预措施减轻ASCVD风险的能力产生积极影响从结核病和其他慢性感染中恢复后。我们将利用概念验证鼠标实验由我们的小组进行的，表明分枝杆菌感染增强了炎症和动脉粥样硬化发育以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我们将在分枝杆菌感染清理后，建立小鼠动脉粥样硬化的进展标准抗生素。在AIM 2中，我们将介绍感染后单核细胞的激活和功能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的主要参与者初步数据表明它们在感染清除率后仍保持启动。成功完成拟议的研究将允许开发必不可少的鼠标模型，为研究提供基础感染后动脉粥样硬化的机制。我们将使用拟议的模型和发现来支持R01 旨在解密动脉粥样硬化后感染后进展和潜在免疫的应用机制。我们的结果将通过提供一个模型来调查，从而产生广泛的转化科学影响 ASCVD风险的机制和其他炎症驱动疾病的幸存者中的慢性疾病感染。