Mechanisms of PCSK9 in endothelial aging

PCSK9在内皮衰老中的机制

基本信息

批准号：
10350785
负责人：
Zufeng Ding
金额：
$ 22.8万
依托单位：
UNIV OF ARKANSAS FOR MED SCIS
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：
2022-01-01 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10350785
关键词：
Address Affect Age Aging Animals Antioxidants Aorta Apoptosis Apoptotic Binding Biological Assay Blood Vessels CASP1 gene Cardiovascular Diseases Cardiovascular system Cell Aging Cell physiology Cells Cerebrovascular Disorders Cessation of life Clinical Trials DNA Damage Data Development Disease Drug Design Elderly Endothelial Cells Endothelium Event Family Genotype Goals Human Impairment Inflammasome Inflammatory Inflammatory Response Interleukin-1 Interleukin-1 beta Interleukin-18 Knock-out Low Density Lipoprotein Receptor Mediating Membrane Mitochondria Mitochondrial DNA Mus NOS3 gene Outcome Participant Pathogenesis Pathway interactions Patients Persons Phagocytes Pharmaceutical Preparations Play Process Public Health Reactive Oxygen Species Reporting Research Role Serine Protease Serum Signal Pathway Signal Transduction Testing Transgenic Organisms Up-Regulation Vascular Endothelial Cell World Health Organization aged aortic arch base beta-Galactosidase cytokine design experience human old age (65+)inhibitor innovation insight knock-down new therapeutic target novel prevent senescence therapeutic target therapeutically effective

项目摘要

PROJECT SUMMARY/ABSTRACT Cardiovascular and cerebrovascular diseases are the leading cause of global deaths contributing to as much as one third of deaths, according to the World Health Organization's Global Status Report on Noncommunicable Diseases. Endothelial cell senescence and subsequent endothelial aging are closely associated with cardiovascular and cerebrovascular diseases in older people. PCSK9 is a serine protease that plays an important role in regulating inflammatory responses and programmed cell death. We recently reported that PCSK9 contributes to mitochondrial DNA damage, NLRP3 inflammasome activation, and pyroptosis (an inflammatory form of programmed cell death), leading to the release of pro-inflammatory cytokines IL-1β and IL-18. In addition, we found that MerTK, a marker for efferocytosis, is highly expressed in young endothelial cells while inhibited in old endothelial cells; efferocytosis is an important process by which apoptotic cells are removed by phagocytes. Based on our preliminary studies, the central hypothesis to be tested in this project is that aging-mediated PCSK9 upregulation impairs efferocytosis showing failed clearance of apoptotic cells, induces pyroptosis, and contributes to endothelial cell senescence and subsequent endothelial aging. Our long-term goal is to dissect the relationship between PCSK9, impaired efferocytosis, upregulated pyroptosis, and its role in the development of endothelial aging. Our specific aims are: Aim 1 - Determine the contribution of endothelial cell-secreted PCSK9 to endothelial aging; Aim 2 - Define the role of PCSK9 in regulating efferocytosis; and Aim 3 - Define the role of PCSK9 in regulating pyroptosis. The proposed research is innovative because it will connect PCSK9 with impaired efferocytosis and upregulated pyroptosis in endothelial cells and evaluate the contribution of endothelial cell-secreted PCSK9 to endothelial aging. Insight into the novel mechanism of mitochondrial DNA damage may identify novel ideas for drugs designed to control impaired efferocytosis, targeted at mtDNA damage.

项目概要/摘要心脑血管疾病是全球死亡的主要原因根据世界卫生组织的全球非传染性疾病状况报告，三分之一的死亡内皮细胞衰老和随后的内皮老化与疾病密切相关。 PCSK9是一种在老年人心脑血管疾病中发挥重要作用的丝氨酸蛋白酶。我们最近报道了 PCSK9 在调节炎症反应和程序性细胞死亡中的作用。导致线粒体 DNA 损伤、NLRP3 炎性体激活和细胞焦亡（一种炎症形式的程序性细胞死亡），导致促炎细胞因子 IL-1β 和 IL-18 的释放。我们发现 MerTK（胞吞作用的标志物）在年轻内皮细胞中高表达，而在老内皮细胞；胞吞作用是吞噬细胞清除凋亡细胞的重要过程。根据我们的初步研究，本项目要测试的中心假设是衰老介导的 PCSK9 上调会损害胞吞作用，显示凋亡细胞清除失败，诱导细胞焦亡，并且有助于内皮细胞衰老和随后的内皮老化。 PCSK9、胞吞作用受损、细胞焦亡上调之间的关系及其在发育中的作用我们的具体目标是：目标 1 - 确定内皮细胞分泌的 PCSK9 的贡献。目标 2 - 定义 PCSK9 在调节胞吞作用中的作用；目标 3 - 定义 PCSK9 的作用； PCSK9 在调节细胞焦亡方面的研究具有创新性，因为它将 PCSK9 与细胞焦亡联系起来。内皮细胞胞吞作用受损和焦亡上调，并评估内皮细胞的贡献细胞分泌的 PCSK9 与内皮衰老的关系可能会深入了解线粒体 DNA 损伤的新机制。确定旨在控制受损胞吞作用、针对 mtDNA 损伤的药物的新想法。