The Role of Mitochondrial DNA in Innate Immune Activation after Sudden CardiacArrest

线粒体 DNA 在心脏骤停后先天免疫激活中的作用

基本信息

批准号：
10480315
负责人：
Cody Rutledge
金额：
--
依托单位：
VETERANS HEALTH ADMINISTRATION
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：
2022-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10480315
关键词：
Admission activity Adult Affect American Anti-Inflammatory Agents Bacterial DNA Cardiac Cardiac Myocytes Cardiac Volume Cardiogenic Shock Cardiovascular Diseases Cell Death Cell model Cells Characteristics Chemicals Clinical Clinical Research Cyclic GMP Cytokine Signaling Cytoplasm DNA Damage DNA copy number Data Development Disease model Flow Cytometry Functional disorder Future Genes Goals Grant Heart Heart Arrest Heart Diseases High Prevalence Hospital Administration Hospitalization Hospitals Human Hypoxia Immune response Immune signaling In Vitro Induced Heart Arrest Inflammation Inflammatory Inflammatory Response Injury Innate Immune Response Innate Immune System Intensive Care Ischemia Knock-out Knockout Mice Lead Mediating Mentorship Microscopy Mitochondria Mitochondrial DNA Molecular Multiple Organ Failure Mus Myocardial dysfunction Myocarditis Myocardium Nuclear Operative Surgical Procedures Organ Outcome Pathologic Patients Pattern Peripheral Permeability Pharmaceutical Preparations Pharmacology Physicians Proteins Recovery Reperfusion Injury Research Resuscitation Role Scientist Septic Shock Serum Signal Pathway Signal Transduction Stimulator of Interferon Genes Structure Survivors Syndrome System Testing Therapeutic Intervention Time Tissues Training Transgenic Mice Translational trial United States United States Department of Veterans Affairs Universities Veterans Work career career development circulating DNA clinically relevant cytokine experimental study extracellular factor A heart function immune activation improved improved outcome in vivo Model inflammatory marker military veteran mortality mouse model mtTF1 transcription factor novel overexpression preservation prevent research and development response sudden cardiac death survival outcome therapeutic target transcription factor transcriptome sequencing

项目摘要

ABSTRACT Sudden cardiac arrest is highly prevalent among hospitalized veterans and results in overwhelming mortality. Unfortunately, there are no pharmacologic therapies that have been shown to reliably increase survival after sudden cardiac arrest. Survivors of sudden cardiac arrest typically have systemic organ damage requiring intensive care in the hospital. The majority of these patients have reduced cardiac function and one quarter of these patients die from cardiogenic shock. Cardiac inflammation is thought to contribute to this dysfunction and is likely driven by damage associated molecular patterns (DAMPs). One prominent DAMP is mitochondrial DNA (mtDNA). Preliminary work in our lab has shown that strategies aimed at preserving mtDNA integrity, including overexpression of mitochondrial transcription factor A (TFAM), are protective to cardiac function in a mouse model of sudden cardiac arrest. TFAM is a nuclear gene that regulates mtDNA expression, packaging, and copy number and is known to be protective in a number of heart disease models. My overarching hypothesis is that ischemia-reperfusion injury from cardiac arrest results in mtDNA release, which triggers an inflammatory response in the heart, and that this response is dependent upon cGAS/STING signaling. To explore this hypothesis, I will pursue three specific aims. In Aim 1, I will explore the mechanism by which mtDNA is released using microscopy in vitro and confirm these changes in an in vivo model of sudden cardiac arrest. In Aim 2, I will use transgenic mouse models to manipulate TFAM to affect mtDNA release and also knock-out STING signaling to explore the relationship between mtDNA release and inflammation after sudden cardiac arrest. In Aim 3, I will characterize the inflammatory response in the heart after sudden cardiac arrest and manipulate cGAS/STING signaling to evaluate cGAS/STING mediated inflammatory changes. Together, these aims will evaluate the role of mtDNA release following sudden cardiac arrest and its role in innate immune signaling, which may guide future therapies for human studies. This work will support my goal of transitioning into an independent research career as a physician-scientist studying mitochondrial changes in cardiovascular disease. This grant will support continued research and career development at both the Veterans Administration Hospital in Pittsburgh and the University of Pittsburgh, including coursework, career mentorship, and scientific training aimed at transitioning to independence as a physician scientist in the Veterans Administration system.

抽象的心脏骤停在住院退伍军人中非常普遍，导致极高的死亡率。不幸的是，没有任何药物疗法被证明可以可靠地提高术后生存率。心脏骤停。心脏骤停的幸存者通常会出现全身器官损伤，需要在医院的重症监护室。这些患者中的大多数患者心功能下降，四分之一的患者心功能下降。这些患者死于心源性休克。心脏炎症被认为是导致这种功能障碍的原因之一可能是由损伤相关分子模式 (DAMP) 驱动的。一种重要的 DAMP 是线粒体 DNA（线粒体DNA）。我们实验室的初步工作表明，旨在保护 mtDNA 完整性的策略，包括线粒体转录因子 A (TFAM) 的过度表达，对心脏功能有保护作用心脏骤停小鼠模型。 TFAM是调节mtDNA表达、包装、和拷贝数，并且已知在许多心脏病模型中具有保护作用。我的首要假设是心脏骤停引起的缺血再灌注损伤会导致 mtDNA 释放，它会引发心脏的炎症反应，并且这种反应取决于 cGAS/STING 发信号。为了探索这个假设，我将追求三个具体目标。在目标1中，我将探索其机制通过体外显微镜释放 mtDNA，并在体内模型中确认这些变化心脏骤停。在目标2中，我将使用转基因小鼠模型来操纵TFAM来影响mtDNA 释放并敲除 STING 信号，以探索 mtDNA 释放与心脏骤停后出现炎症。在目标 3 中，我将描述心脏炎症反应的特征心脏骤停后并操纵 cGAS/STING 信号传导来评估 cGAS/STING 介导的炎症变化。总之，这些目标将评估心脏骤停后 mtDNA 释放的作用及其在先天免疫信号传导，可能指导未来的人类研究疗法。这项工作将支持我的目标作为一名研究线粒体变化的医师科学家过渡到独立研究生涯心血管疾病。这笔赠款将支持两所大学的持续研究和职业发展匹兹堡退伍军人管理局医院和匹兹堡大学，包括课程、职业指导和科学培训，旨在过渡为独立的医师科学家退伍军人管理系统。