Role of Aging on cardiac macrophage dysfunction and heart failure during infection

衰老对感染期间心脏巨噬细胞功能障碍和心力衰竭的作用

• 批准号: 10447405
• 负责人: Murugesan Rajaram
• 金额: $ 23.63万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10447405
• 关键词: Age; Aging; Apoptotic; Arrhythmia; Biology of Aging; Cardiac; Cardiac Myocytes; Cardiac Output; Cardiac development; Cardiac health; Cardiovascular Diseases; Cardiovascular system; Cell Aging; Cells; Cessation of life; Choristoma; Chromatin; Chronic; Collagen; Complication; Data; Data Set; Dementia; Development; Diabetes Mellitus; Disease; Distress; Elderly; Embryo; Epigenetic Process; Exploratory/Developmental Grant; Fibrosis; Frequencies; Functional disorder; Goals; Heart; Heart Diseases; Heart failure; Heterogeneity; Immune; Immune response; Immune system; Immunologic Surveillance; Immunologics; Impairment; Individual; Infection; Infiltration; Inflammaging; Inflammation; Inflammatory; Ischemia; Kidney Diseases; Knowledge; Lead; Left Ventricular Hypertrophy; Longevity; Lung infections; Malignant Neoplasms; Measurement; Mediating; Mediator of activation protein; Medicare; Mission; Modeling; Molecular; Morphology; Mus; Mycobacterium Infections; Myelogenous; Myeloid Cells; Myocardial dysfunction; Myocardium; Natural Immunity; Opportunistic Infections; Pathogenesis; Pathology; Performance; Persons; Pharmacology; Phenotype; Population; Predisposition; Process; Prognostic Factor; Proteins; Public Health; Publishing; RNA; Research; Resolution; Resources; Risk Factors; Role; Technology; Testing; Tissues; United States; XCL1 gene; adaptive immune response; age related; aged; aging population; base; beneficiary; cardiovascular disorder therapy; data integration; decubitus ulcer; functional group; heart damage; heart function; high risk; macrophage; monocyte; mortality risk; multi-drug resistant pathogen; multiple omics; non-tuberculosis mycobacteria; novel strategies; novel therapeutics; opportunistic pathogen; pathogen; prevent; programs; receptor; tissue repair; trafficking

The United States elderly population is predicted to increase three-fold by 2050, reaching over 85 million. The burden of heart failure will also increase due to age associated cardiovascular and inflammatory diseases. For example, the elderly are more susceptible to cardiac infection due to chronic inflammation, termed “inflamm- aging.” Opportunistic infections of these individuals, which would normally be easily cleared, can result in severe cardiac distress, and death. Indeed, aging is a major prognostic factor for contraction of non-tuberculous mycobacterial (NTM) disease, and associated dissemination to the heart. There is also a clear need for treatment options, as there is up to a 40% risk for death in elderly persons with NTM infection. Innate and adaptive immune responses are tightly regulated in the heart to prevent maladaptive inflammation, which may malfunction during inflammaging. Recently we have demonstrated that infection with an opportunistic pathogen, NTM, predisposes aged mice to cardiac arrhythmia (Ageing Cell 2019). As there are currently no effective pharmacological therapies for cardiac NTM infection within the elderly, we believe understanding the mechanisms involved in associated inflammation and phenotypic changes could assist in rational therapy choice. We have discovered that, during infection of old hearts, beneficial CCR2-, MerTK+ cardiac resident macrophages (CRMs) are replaced with inflammatory myeloid-derived cells. Thus we hypothesize that inflammaging causes enhanced myeloid cell trafficking, epigenetic reprograming and phenotypic switch in CRMs phenotypes, and defective tissue repair, processes that contribute to infection-associated cardiac dysfunction. The goals of this research program are to: 1) Determine cellular and epigenetic identities of aged cardiac myeloid cells during infection, and 2) Determine whether enhancing the expression of MerTK in CRMs provides cardio protection in old mice. We will use young (2-3 months) and old (18-24 months) mice to study the impact of NTM in cardiac dysfunction. Application of multi-omics (Single Cell RNA and ATAC sequencing) technology will provide a general resource for studying infection, and aging, within the heart. Overall, our mission is to define cardiac macrophage subsets, identify the mechanism of macrophage phenotypic changes and its role during infection in young and old mice. Given the large, and growing, public health burden of opportunistic infection within aging hearts, and a lack of knowledge about fundamental immunological control mechanisms, this project is ideally suited for the R21 mechanism. Further, identifying macrophage populations responsible for aging-related dysfunction could lead to new approaches and drugs to treat cardiac dysfunction in elderly.

预计到2050年，美国老年人口将增加三倍，达到8500多万。的 心力衰竭的负担也将由于年龄相关的心血管和炎性疾病而增加。为 例如，由于慢性炎症，老年人更容易受到心脏感染，称为“炎症”， 老化”这些人的寄生虫感染通常很容易清除，但可能导致严重的 心脏窘迫和死亡事实上，年龄是非结核性肺结核收缩的一个主要预后因素。 分枝杆菌（NTM）疾病，以及相关的心脏传播。显然也需要治疗 选择，因为NTM感染的老年人死亡风险高达40%。 先天性和适应性免疫反应在心脏中受到严格调节，以防止适应不良的炎症， 其可能在发炎期间发生故障。最近我们已经证明，机会性感染 病原体NTM使老年小鼠易患心律失常（Ageing Cell 2019）。由于目前没有 老年人心脏NTM感染的有效药物治疗，我们相信， 相关炎症和表型变化的机制可能有助于合理的治疗选择。 我们已经发现，在旧心脏感染期间，有益的CCR 2-、MerTK+心脏驻留巨噬细胞 （CRM）被炎性骨髓源性细胞取代。因此，我们假设炎症导致 CRMs表型中增强的骨髓细胞运输、表观遗传重编程和表型转换，以及 有缺陷的组织修复，导致感染相关的心脏功能障碍的过程。这个的目标 研究计划是：1）确定老年心肌髓系细胞的细胞和表观遗传特性， 2）确定在CRMs中增强MerTK的表达是否提供心脏保护， 老老鼠我们将使用年轻（2-3个月）和老年（18-24个月）小鼠研究NTM对心脏的影响， 功能障碍多组学（单细胞RNA和ATAC测序）技术的应用将提供 研究心脏内感染和衰老的一般资源。总的来说，我们的使命是定义心脏 巨噬细胞亚群，确定巨噬细胞表型变化的机制及其在感染过程中的作用 在年轻和年老的老鼠身上。考虑到老龄化过程中机会性感染的巨大且不断增长的公共卫生负担， 心脏，以及缺乏基本免疫控制机制的知识，这个项目是理想的 适用于R21机制。此外，识别负责衰老相关的巨噬细胞群体， 心功能不全可能导致治疗老年人心功能不全的新方法和药物。