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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.

项目总结