ACE and myeloid cell metabolism

ACE 和骨髓细胞代谢

基本信息

批准号：
10570941
负责人：
KENNETH E BERNSTEIN
金额：
$ 56.64万
依托单位：
CEDARS-SINAI MEDICAL CENTER
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：
2022-02-11 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10570941
关键词：
ACE2 Acute Address Affect Angiotensin II Angiotensin-Converting Enzyme Inhibitors Angiotensins Antibacterial Response Biochemical Blood Pressure Cardiovascular system Cell Respiration Cell physiology Cells Cellular Metabolic Process Chemicals Chronic Chronic Disease Clinical Data Disease Effectiveness Enzyme Induction Enzymes Genetic Goals Human Immune Immune response Infection Inflammatory Innate Immune Response Knock-out Learning Link Lipids Macrophage Malignant Neoplasms Mass Spectrum Analysis Mediating Medical Research Metabolic Metabolism Mus Myelogenous Myeloid Cells Oxidative Phosphorylation PPAR alpha Paper Peptides Peptidyl-Dipeptidase A Phenotype Process Production Proteins Ramipril Role Solid Superoxides adaptive immune response autocrine enzyme activity enzyme mechanism enzyme substrate fighting immune function lipid metabolism neutrophil novel overexpression paracrine response transcription factor tumor volunteer

项目摘要

A long sought goal of medical research is to identify ways to increase the effectiveness of the immune response. Here, we present a means of increasing myeloid cell function by increasing cell expression of angiotensin converting enzyme (ACE). We show that 1) under natural circumstances in both humans and mice, myeloid cells increase their production of ACE in response to immune challenge. This is an adaptive response that allows the cells to better respond to the challenge. 2) When this process is exaggerated by using genetic means to augment ACE expression in either macrophages or neutrophils, the result is a marked increase in the ability of mice to mount both an innate and adaptive immune response against a variety of immune challenges. This increase in response is directly due to the catalytic activity of the over-expressed ACE protein. 3) The enhanced immune response is the result of ACE-induced metabolic changes that increase oxidative phosphorylation and increase myeloid cell ATP. This is quite different from the well described myeloid metabolic effects of LPS. That ACE affects cell levels of ATP is a very new finding based on mass spectrometry and chemical analysis of ATP levels in two lines of mice. In contrast, myeloid cells genetically lacking ACE have reduced ATP and reduced immune function. 4) Similar to the genetic ACE KO, ACE inhibitors (ACEi) reduce neutrophil superoxide and anti-bacterial response in both humans and mice. Thus, there is a direct relationship between the level of ACE expression by myeloid cells, myeloid cell ATP content, and effectiveness of the immune response. Understanding how ACE affects myeloid cell immunometabolism will reveal a totally new biochemical means of enhancing myeloid function that might ultimately be manipulated to enhance human response. In Aim 1, we examine the detailed metabolism of myeloid cells with increased ACE expression to identify changes affecting immune function. In Aim 2, we will study the role of the transcription factor PPARα in inducing the immune phenotype of myeloid cells expressing increased ACE. We also ask how ACE activity induces increased cell PPARα. In Aim 3, we study whether ACE acts as an autocrine or paracrine factor and whether we can characterize the peptide product of ACE responsible for affecting cell metabolism and increasing the immune response of myeloid cells.

医学研究的一个长期追求的目标是找到提高治疗有效性的方法。在这里，我们提出了一种通过增加细胞来增强骨髓细胞功能的方法。我们表明1）在自然条件下血管紧张素转换酶（ACE）的表达。无论是人类还是小鼠，骨髓细胞都会增加 ACE 的产生以应对免疫这是一种适应性反应，可以让细胞更好地应对挑战 2)。当这个过程通过使用遗传手段来增强 ACE 表达而被夸大时巨噬细胞或中性粒细胞，其结果是小鼠的能力显着增加针对各种免疫挑战的先天性和适应性免疫反应的增加。反应直接归因于过表达的 ACE 蛋白的催化活性 3) 增强。免疫反应是 ACE 诱导的代谢变化的结果，这些变化会增加氧化磷酸化并增加骨髓细胞 ATP 这与充分描述的骨髓细胞有很大不同。 LPS 的代谢效应是基于质量的一个非常新的发现。相比之下，骨髓细胞中两系小鼠的 ATP 水平的光谱测定和化学分析。遗传性缺乏ACE会减少ATP并降低免疫功能 4）与遗传性ACE类似。 KO、ACE 抑制剂 (ACEi) 可减少人类中性粒细胞超氧化物和抗菌反应因此，骨髓细胞的 ACE 表达水平之间存在直接关系，骨髓细胞 ATP 含量以及免疫反应的有效性。了解 ACE 如何影响。骨髓细胞免疫代谢将揭示增强骨髓细胞的全新生化手段最终可能被操纵以增强人类反应的功能。在目标 1 中，我们研究了 ACE 表达增加的骨髓细胞的详细代谢，以确定影响的变化在目标 2 中，我们将研究转录因子 PPARα 在诱导免疫功能中的作用。表达 ACE 增加的骨髓细胞的免疫表型我们还询问 ACE 活性如何诱导。在目标 3 中，我们研究 ACE 是否作为自分泌因子或旁分泌因子起作用。我们能否表征负责影响细胞代谢的 ACE 肽产物以及增加骨髓细胞的免疫反应。