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Mechanisms of PCSK9 in endothelial aging

PCSK9在内皮衰老中的机制

基本信息

批准号：
10544746
负责人：
Zufeng Ding
金额：
$ 19万
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/10544746
关键词：
Acceleration Address Affect Age Aging Animals Antioxidants Aorta Apoptosis Apoptotic Binding Biological Assay Blood Vessels CASP1 gene Cardiovascular Diseases Cardiovascular system Cell Aging Cell Separation Cell physiology Cell secretion Cells Cerebrovascular Disorders Cessation of life Clinical Trials DNA Damage Data Development Disease Drug Design Elderly Endothelial Cells Endothelium Event Family Genotype Goals Human IL18 gene Impairment Inflammasome Inflammatory Inflammatory Response Interleukin-1 Interleukin-1 beta Knock-out Knockout Mice 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 Mice Transgenic Organisms Up-Regulation Vascular Endothelial Cell World Health Organization aged aortic arch 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.

项目总结/摘要心血管和脑血管疾病是全球死亡的主要原因，根据世界卫生组织的《非传染性疾病全球状况报告》，疾病内皮细胞衰老和随后的内皮老化与老年人心脑血管疾病。PCSK 9是一种丝氨酸蛋白酶，在细胞内起重要作用。调节炎症反应和程序性细胞死亡的作用。我们最近报道了PCSK 9 导致线粒体DNA损伤、NLRP 3炎性体激活和焦亡（炎性细胞凋亡）。程序性细胞死亡的形式），导致促炎细胞因子IL-1β和IL-18的释放。此外，本发明还提供了一种方法，我们发现，MerTK，一种红细胞增多症的标志物，在年轻的内皮细胞中高度表达，而在新生的内皮细胞中被抑制。衰老的内皮细胞;吞噬作用是凋亡细胞被吞噬细胞清除的重要过程。基于我们的初步研究，本项目要检验的中心假设是，衰老介导的PCSK 9 上调损害细胞凋亡，显示凋亡细胞清除失败，诱导焦亡，导致内皮细胞衰老和随后的内皮老化。我们的长期目标是剖析 PCSK 9、受损的红细胞增多症、上调的焦亡之间的关系及其在发育中的作用内皮细胞老化。我们的具体目标是：目标1 -确定内皮细胞分泌的PCSK 9的贡献目的2 -确定PCSK 9在调节红细胞增多症中的作用;目的3 -确定 PCSK 9在调节焦亡中的作用拟议的研究是创新的，因为它将PCSK 9与内皮细胞中受损的红细胞增多和上调的焦亡，并评估内皮细胞的贡献。细胞分泌的PCSK 9对内皮老化的影响。深入了解线粒体DNA损伤的新机制可能确定新的药物设计思路，以控制受损的线粒体DNA损伤为目标的红细胞增多症。