权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Inflammasome-Mediated Cardiac Cell Death in the Aged Female Rat Heart

老年雌性大鼠心脏中炎症小体介导的心肌细胞死亡

基本信息

批准号：
10398193
负责人：
DONNA HOPE KORZICK
金额：
$ 20.06万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10398193
关键词：
3-Dimensional Acute Acute myocardial infarction Adult Age Aging American Attenuated CASP1 gene Cardiac Cause of Death Cell Death Cells Cessation of life Chronic Clinical Coronary artery Data Development Dichloromethylene Diphosphonate Disease Progression Estrogens Face Female Future Goals Heart Heart Diseases Human IL18 gene Immune Immune Targeting Immune response Immune signaling Impairment Infarction Inflammasome Inflammation Inflammatory Interleukin-1 beta Intervention Knock-out Laboratories Ligation Link Liposomes Mediating Menopause Mitochondria Mitochondrial DNA Modeling Molecular Myocardial Infarction Myocarditis Natural History Oxidative Stress Pathogenesis Pattern Phenotype Population Postmenopause Production Quality Control Rattus Regulation Reperfusion Injury Reperfusion Therapy Resolution Respiration Rodent Model Role Scheme Severities Signal Transduction Testing Time Tumor-infiltrating immune cells Ventricular Remodeling Woman Work age effect aged cardioprotection cardiovascular disorder risk cytokine heart disease prevention immunological intervention immunoregulation improved inflammatory milieu inhibitor ischemic injury macrophage male marenostrin mitochondrial autophagy mortality novel novel therapeutics older women protective efficacy receptor reconstruction response small molecule small molecule inhibitor therapeutic target

项目摘要

Project Summary Acute myocardial infarction (AMI) is the leading cause of death in post-menopausal women, but how age- associated estrogen loss impacts the intersection of cardiac ischemic-reperfusion (I/R) injury, NLRP3 inflammasome signaling and subsequent AMI pathogenesis is untested. Promising feasibility data suggest that NLRP3 inflammasome hyperactivation and dysregulated cardiac mitochondrial quality control may create a toxic feed forward circuit to exacerbate proinflammatory responses and AMI progression in aged females. Age- associated chronic inflammation may amplify oxidative stress through impaired macrophage polarization. We will identify and characterize key age-associated changes in NLRP3 immune signaling that promote pyroptosis and infarct progression, and determine whether insufficient cardiac mitophagy is a driver of NLRP3 inflammasome hyperactivation following I/R injury in aged females (Aim 1). We will next determine if acute NLRP3 inflammasome suppression using a small molecule inhibitor, with and without macrophage depletion, confers cardioprotection through a mechanism involving reparative M2 macrophage phenotypic expression and protective cardiac mitochondrial quality control (Aim 2). We propose that targeted NLRP3 inflammasome inhibition will rescue the post-menopausal aged heart through unique and overlapping mechanisms involving cardiac macrophage polarization, mitophagy, and limiting mitochondrial-derived danger associated molecular patterns (DAMPs). The proposed studies are a logical extension of ongoing work in our laboratory, which seeks to define the effects of age-associated estrogen loss on cardiac I/R injury. F344 female rats will be ovariectomized at 15 mo and aged to 24 mo to better mimic human menopause, NLRP3 knock out rats for proof of concept, and adult and aged male rats for clinical comparison. Coronary artery ligation will be used to induce AMI with variable reperfusion over 7 days to test our specific aims in cardiac immune cell subsets and mitochondria. The findings from this study will be invaluable in establishing a role for NLRP3 inflammasome- mediated regulation of I/R injury in the aged female heart and strongly support the NLRP3 inflammasome as a therapeutic target for AMI reduction in older post-menopausal women. We will determine, for the first time, the contribution and mechanism by which NLRP3 inflammasome hyperactivation impacts vulnerability to AMI in aged female (and male) rats.

项目摘要急性心肌梗死(AMI)是绝经后妇女的主要死亡原因，但年龄- 相关的雌激素丢失影响心脏缺血/再灌注损伤的交叉点，NLRP3 炎症体信号和随后的急性心肌梗死发病机制尚未得到证实。前景看好的可行性数据表明 NLRP3炎症体过度激活和心肌线粒体质量控制失调可能造成毒性前馈回路加剧老年女性的促炎反应和急性心肌梗死进展。年龄- 相关的慢性炎症可能通过受损的巨噬细胞极化放大氧化应激。我们将识别和表征促进下垂的NLRP3免疫信号中与年龄相关的关键变化和梗塞进展，并确定心脏吞噬功能不足是否是NLRP3的驱动因素老年女性I/R损伤后炎性小体过度激活(目标1)。接下来我们将确定急性呼吸道感染使用小分子抑制剂抑制NLRP3炎症体，伴和不伴巨噬细胞耗竭，通过一种涉及修复性M2巨噬细胞表型表达和保护性心肌线粒体质量控制(目标2)。我们建议靶向NLRP3炎症体抑制将通过独特和重叠的机制拯救绝经后老化的心脏心肌巨噬细胞极化、有丝分裂和限制性线粒体衍生危险相关分子图案(湿气)。拟议的研究是我们实验室正在进行的工作的合乎逻辑的延伸，该实验室寻求目的：探讨年龄相关性雌激素丢失对心脏I/R损伤的影响。F344雌性大鼠将被为了更好地模仿人类更年期，NLRP3基因敲除大鼠作为证据，在15个月时切除卵巢，年龄至24个月并与成年和老年雄性大鼠进行临床对比。冠状动脉结扎将被用来诱导用超过7天的可变再灌注来测试我们在心脏免疫细胞亚群和线粒体。这项研究的发现对于确定NLRP3炎症体的作用将是非常有价值的。 NLRP3炎症体对老年女性心脏I/R损伤的调节作用老年绝经后妇女急性心肌梗死减少的治疗目标。我们将第一次确定 NLRP3炎性小体过度激活对老年人急性心肌梗死易感性的影响及其机制雌性(和雄性)大鼠。