Mitochondrial DNA, chronic stress, and inflammation

线粒体 DNA、慢性压力和炎症

基本信息

批准号：
10664066
负责人：
Anilkumar Pillai
金额：
$ 44.57万
依托单位：
UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
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：
2022-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10664066
关键词：
2019-nCoV Adaptor Signaling Protein Affect Animal Model Attenuated Behavioral CD4 Positive T Lymphocytes Cells Chronic Chronic stress Cytosine DNA Data Deoxyribonuclease I Development Dissection Emotional Exhibits Exposure to Functional disorder Genetic Goals Guanine Immune system Impairment Inflammation Inflammatory Response Intervention Knockout Mice Laboratories Mediating Mental Health Mental disorders Microglia Mission Mitochondria Mitochondrial DNA Mus National Institute of Mental Health Neurons Pharmacology Play Prefrontal Cortex Process Public Health Risk Factors Role SARS-CoV-2 infection Signal Transduction Signaling Protein Social Behavior Stress Stressful Event T-Lymphocyte TLR9 gene Testing Therapeutic Treatment Efficacy United States National Institutes of Health Work antagonist chemokine cytokine experimental study extracellular fetal human model improved inorganic phosphate insight mental health related disorder neuroinflammation neuropsychiatric disorder neuropsychiatry neurotransmission novel novel therapeutic intervention prevent response restraint stress social social deficits

项目摘要

Chronic stress is a risk factor for the development of multiple psychiatric disorders for which current treatments are inadequate. Evidence from our laboratory and others suggest that chronic stress can also provoke elevated inflammation and exaggerated inflammatory responses in both humans and animal models. However, the underlying mechanisms are not well understood. Mitochondria become damaged and dysfunctional following chronic stress conditions raising the question of whether neuroinflammation associated with chronic stress-related neuropsychiatric conditions is due to mitochondria-induced inflammation. By removing damaged mitochondria, mitophagy plays a central role in preventing inflammation. When this process is impaired, mtDNA is released and the extracellular cell free mtDNA (cf-mtDNA) promotes Toll-like receptor 9 (TLR9) signaling to activate immune system. Our recent study found that mice exposed to chronic restraint stress (RS) exhibit neuroinflammation and social behavior deficits. Our preliminary data show that depletion of cf-mtDNA with DNase I treatment attenuates RS-induced deficits in social behavior and increases in proinflammatory markers in the prefrontal cortex (PFC). Furthermore, we found that mtDNA-induced deficits in social behavior are TLR9-dependent. Also, RS induced significant increases in TLR9 expression in microglia and neurons. Among the various mitophagy-related molecules, activation of Mitochondrial antiviral-signaling protein (MAVS, a mitochondrial adaptor protein)signaling results in proinflammatory signaling. Our preliminary findings showed that RS-induced increase in cf-mtDNA is attenuated in MAVS KO mice. Also, we found impaired mitophagy in CD4+, but not CDS+ T cells following RS. We hypothesize that increased levels of mtDNA from CD4• T cells contribute to RS-induced neuroinflammation and social behavior deficits via TLR9 activation. Aim 1 will determine whether RS-induced mtDNA release drives neuroinflammation and reduced social behavior. Aim 2 will examine whether mtDNA-mediated activation of TLR9 on neurons promotes social behavior deficits following RS. Aim 3 will examine whether mtDNA release induced by RS is dependent on mitophagy. If successful, our project will create new developments in understanding the mechanism mediating stress-induced neuroinflammation social behavior deficits, and thereby allow the development of pharmacological approaches to inhibit mtDNA release, neutralize extracellular cf-mtDNA, or inhibit TLR9 activation in stress-related mental health disorders.

慢性压力是多种精神疾病发展的危险因素，目前的治疗方法不足，我们实验室和其他实验室的证据表明，慢性压力也会引起人类和动物模型的炎症升高和炎症反应加剧。线粒体在慢性应激条件下受损和功能障碍的机制尚不清楚，这引发了一个问题：与慢性应激相关的神经精神疾病相关的神经炎症是否是由线粒体诱导的炎症引起的，线粒体自噬在其中发挥着核心作用。当这一过程受损时，线粒体 DNA 会被释放，并且细胞外游离线粒体 DNA (cf-mtDNA) 会促进 Toll 样受体 9 (TLR9) 信号传导，从而激活免疫系统。 (RS) 表现出神经炎症和社会行为缺陷。我们的初步数据表明，用 DNase I 治疗消除 cf-mtDNA 可减轻 RS 引起的社会行为缺陷和促炎症标记物的增加。此外，我们发现 mtDNA 诱导的社会行为缺陷是 TLR9 依赖性的，并且在各种线粒体自噬相关分子中，RS 还诱导 TLR9 表达显着增加。我们的初步研究结果表明，RS 诱导的 cf-mtDNA 增加是由抗病毒信号蛋白（MAVS，一种线粒体衔接蛋白）信号传导导致的。此外，我们发现 RS 后 CD4+ T 细胞线粒体自噬受损，但 CD4• T 细胞 mtDNA 水平增加，通过 TLR9 Aim Aim 激活导致 RS 诱导的神经炎症和社会行为缺陷。目标 1 将确定 RS 诱导的 mtDNA 释放是否会导致神经炎症并减少社会行为。目标 2 将检查 mtDNA 是否介导神经元上的 TLR9 激活。目标 3 将检查 RS 诱导的 mtDNA 释放是否依赖于线粒体自噬，如果成功，我们的项目将在了解介导压力诱导的神经炎症社会行为缺陷的机制方面取得新的进展，从而允许发展。在压力相关的精神健康障碍中抑制 mtDNA 释放、中和细胞外 cf-mtDNA 或抑制 TLR9 激活的药理学方法。