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

基本信息

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
项目类别：
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

项目摘要

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（ELS）通常伴随着成年的不利健康结果有更多的严重性，例如全身性红斑狼疮（SLE）随着ELS暴露和CVD的增加，自身免疫性和心脏免疫性的风险（CVD）增加。在SLE的早期死亡率的主要原因。与EL的共存与SLE中高高高高心脏病有关。尽管麻风病与ELS患者相关的疾病活性联系在一起，但尚未在临床前研究与EL的啮齿动物模型相结合。促炎的表型和血管功能障碍。早期断奶（MSEW），我们在超氧化物上观察到主动脉内皮功能障碍并增加在加法的艾adia中，f4/80+巨噬细胞的数量，一种先天免疫细胞在我们期望的pristane诱导的MSEW小鼠中，功能障碍和主动脉刚度被夸大了血管功能的障碍是在MSEW动物中造成巨噬细胞的存在数据表明，MSEW小鼠中存在mitchondrial功能障碍，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。通过线粒体衍生的超氧化物的SLE小鼠模型的发展和严重性生产和激活的促炎巨噬细胞我们将确定巨噬细胞是否介导了EL中主动脉疾病的发展。和RNA测序以确定MSEW和对照小鼠之间的免疫激活差异与对照组相比，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。 MSEW方案以确定氧化应激是否与SLE介导的高血有关通过ELS，使用遥测和EL后的血管反应性检查袖子中的CVD标记。我们期望通过封闭线粒体超氧化物后，我们还将测量CVD和疾病参见（i）升高的炎症性巨噬细胞，当不存在时，请减少血管功能障碍，以及（ii）更大的CVD 通过Mitotempol治疗减轻的MSEW SLE小鼠的负担对于开始了解该项目至关重要。 EL在SLE中作为与CVD保持IMune驱动疾病的关键的机械关系并发症与多种疾病的不利健康结果有关。领域对于为患者制定相关和可及的预防策略至关重要研究为ELS驱动的CVD提供了两种潜在的互补途径。