Early Life Stress Promotes an Inflammatory Phenotype Leading to Vascular Impairment and Lupus Nephritis Severity

早期生活压力促进炎症表型，导致血管损伤和狼疮性肾炎严重程度

• 批准号: 10537298
• 负责人: Cailin Kellum
• 金额: $ 3.78万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-22 至 2025-08-21
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10537298
• 关键词: Address; Adolescent; Adult; Animals; Aorta; Aortic Diseases; Autoantibodies; Autoimmune; Autoimmune Diseases; Autoimmunity; Blood; Blood Vessels; Bone Marrow; Cardiovascular Diseases; Career Choice; Cells; Child Abuse; DNA Damage; Data; Development; Diagnosis; Dichloromethylene Diphosphonate; Disease; Encapsulated; Endothelium; Exposure to; Flow Cytometry; Functional disorder; Goals; Health; Heart Diseases; High Prevalence; Hospitalization; Household; Hypertension; Immune; Immunity; Immunoglobulin G; Immunology; Impairment; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Injections; Intervention; Investigation; Kidney; Knowledge; Life; Link; Lipopolysaccharides; Liposomes; Lupus; Lupus Nephritis; Macrophage Colony-Stimulating Factor; Maintenance; Measures; Mediating; Mediator of activation protein; Mitochondria; Mitochondrial DNA; Modeling; Mus; Outcome; Oxidative Stress; Pathway interactions; Patients; Peritoneal Macrophages; Phenotype; Play; Population; Prevalence; Prevention strategy; Pristane; Production; Protocols documentation; Relaxation; Reporting; Risk; Risk Factors; Risk Marker; Rodent Model; Role; Saline; Scheme; Severities; Severity of illness; Sexual abuse; Stimulus; Superoxides; Systemic Lupus Erythematosus; Telemetry; Testing; Training; Training Support; Tunica Adventitia; Vascular Diseases; Verbally abusive behavior; Weaning; burden of illness; cardiovascular disorder risk; childhood adversity; constriction; cytokine; design; ds-DNA; early life stress; endothelial dysfunction; experience; experimental study; immune activation; in vivo; insight; interest; macrophage; maternal separation; mitochondrial dysfunction; monocyte; mortality; mouse model; novel; pediatric trauma; pre-clinical; prevent; response; skills; transcriptome sequencing

PROJECT SUMMARY Exposure to early life stress (ELS) often is accompanied by adverse health outcomes earlier in adulthood and with more severity such as in the case of Systemic Lupus Erythamateous (SLE), an autoimmune disease. The risk for autoimmunity and cardiovascular disease (CVD) increases with ELS exposure and CVD is the predominant cause for early mortality in SLE patients. This project addresses the gap in knowledge of why coexistence with ELS is associated with higher prevalence and heart disease in SLE. In the case of SLE— despite reports linking worsened disease activity in patients with ELS—there have been no studies in preclinical rodent models of SLE in conjunction with ELS. Several investigations demonstrate that ELS is associated with a pro-inflammatory phenotype and vascular dysfunction. In our mouse model of ELS, maternal separation with early weaning (MSEW), we observed aortic endothelial dysfunction dependent on superoxide and increased numbers of F4/80+ macrophages, an innate immune cell, in the adventitia of the aorta. In addition, vessel dysfunction and aortic stiffness is exaggerated in MSEW mice subjected to pristane induction of SLE. We expect impairment in vascular function is due to proinflammatory macrophage presence in MSEW animals. Preliminary data shows mitochondrial dysfunction is present in MSEW mice indicating the superoxide impacting endothelial dysfunction may be mitochondrial derived. Thus, our overall hypothesis states that ELS accentuates the development and severity of aortic disease in a mouse model of SLE through mitochondrial-derived superoxide production and activated pro-inflammatory macrophages. This project is designed with two specific aims. First, we will determine if macrophages mediate development of aortic disease in ELS. We will use flow cytometry and RNA sequencing to determine immune activation differences between MSEW and control mice. We then will determine if absence of macrophages in vivo prevents MSEW vascular dysfunction compared to controls. Second, studies will address if ELS mediates enhanced development of aortic disease in SLE through mitochondrial superoxide production. The pristane-induced model of SLE will be used in conjunction with the MSEW protocol to determine if oxidative stress, previously linked to SLE-mediated hypertension, is accelerated by ELS. Experiments will examine markers for CVD in SLE using telemetry and vascular reactivity after ELS. We will also measure CVD and disease after blocking mitochondrial superoxide by MitoTEMPOL. We expect to see (i)elevated inflammatory macrophages that, when absent, reduce vascular dysfunction and (ii)a greater CVD burden in MSEW SLE mice reduced by MitoTEMPOL treatment. This project is critical to begin to understand the mechanistic relationship of ELS in SLE as well as crucial for studying immune driven diseases with CVD complications. ELS is associated with adverse health outcomes in a variety of diseases. Advances in the ELS field are essential to developing relevant and accessible intervention and prevention strategies for patients. Our studies provide two potentially complementary pathways for ELS-driven CVD.

项目摘要 暴露于早期生活压力（EL）通常伴随着成年早期的不利健康结果 具有更高的严重性，例如全身性红斑狼疮（SLE），一种自身免疫性疾病。这 自身免疫性和心血管疾病（CVD）的风险随着EL的暴露而增加，CVD是 SLE患者早期死亡的主要原因。该项目解决了为什么 与EL的共存与SLE中的较高患病率和心脏病有关。在SLE的情况下 尽管报道了ELS患者疾病活动恶化的报道，但尚无临床前研究 SLE的啮齿动物模型与EL结合。几项投资表明ELS与 促炎的表型和血管功能障碍。在我们的EL鼠标模型中，Mater与 早期断奶（MSEW），我们观察到主动脉内皮功能障碍取决于超氧化物并增加 在主动脉冒险中，F4/80+巨噬细胞的天生免疫细胞数量。另外，船只 在受SLE的Pristane诱导的MSEW小鼠中，功能障碍和主动脉僵硬量夸大。我们期望 血管功能的损害是由于MSEW动物中促炎性巨噬细胞的存在。初步的 数据表明，线粒体功能障碍在MSEW鼠标中呈现，表明氧化超氧化物影响内皮 功能障碍可能是线粒体衍生的。这，我们的总体假设指出，ELS突显了 通过线粒体衍生的超氧化物的小鼠模型中主动脉疾病的发展和严重程度 生产和激活的促炎巨噬细胞。该项目的设计具有两个特定的目标。第一的， 我们将确定巨噬细胞中主动脉疾病的中位数发生。我们将使用流式细胞仪 和RNA测序以确定MSEW和对照小鼠之间的免疫激活差异。然后我们 与对照组相比，将确定体内巨噬细胞是否不存在MSEW血管功能障碍。 其次，研究将解决ELS是否通过通过 线粒体超氧化物的产生。 Pristane诱导的SLE模型将与 MSEW方案以确定先前与SLE介导的高血压有关的氧化应激是否加速 由Els。实验将使用EL后使用遥测和血管反应性检查SLE中CVD的标记。 我们还将通过Mitotempol阻断线粒体超氧化物后测量CVD和疾病。我们希望 参见（i）升高的炎症巨噬细胞，当不存在时，请减少血管功能障碍，以及（ii）更大的CVD 通过Mitotempol治疗减少的MSEW SLE小鼠中的伯嫩。这个项目对于开始了解 EL在SLE中的机械关系以及对于研究CVD的免疫驱动疾病至关重要 并发症。 ELS与各种疾病中的不良健康结果有关。 ELS的进步 领域对于为患者制定相关且易于获得的干预和预防策略至关重要。我们的 研究为ELS驱动的CVD提供了两种潜在的完整途径。