The role of cell type-specific necroptosis on chronic inflammation and cell non-autonomous effects on other tissues

细胞类型特异性坏死性凋亡对慢性炎症的作用以及细胞对其他组织的非自主效应

• 批准号: 10616037
• 负责人: Deepa Sathyaseelan
• 金额: $ 14.5万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10616037
• 关键词: Adipose tissue; Affect; Age; Aging; Apoptosis; Binding; Biological Assay; Brain; Cell Aging; Cell membrane; Cells; Chronic; Cognition; Data; Disease; Distal; Elderly; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Fatty Liver; Functional disorder; Generations; Genes; HMGB1 gene; Heart; Hepatic Stellate Cell; Hepatocyte; Immune; Impaired cognition; Inflammaging; Inflammation; Inflammatory; Kidney; Knock-in Mouse; Kupffer Cells; Liver; Liver diseases; Lung; Mass Spectrum Analysis; Mediating; Molecular; Mood Disorders; Morbidity - disease rate; Mus; Muscle; Muscular Atrophy; Neuraxis; Pathogenesis; Pathway interactions; Pattern; Persons; Phosphorylation; Phosphotransferases; Play; Population; Prevalence; Protein Kinase; Proteins; RIPK1 gene; RIPK3 gene; Risk Factors; Role; Serum; Skeletal Muscle; Sleep disturbances; Source; Stimulus; Testing; Tissues; Wild Type Mouse; age related; base; cell type; chemokine; chronic liver disease; cytokine; extracellular vesicles; healthspan; inflammatory marker; inhibitor; liver inflammation; liver transplantation; macrophage; mortality; mouse model; muscle form; non-alcoholic; novel; overexpression; sarcopenia; transcriptomics

Project Summary Chronic, low-grade inflammation (inflammaging) is a hallmark of aging and is one of the ‘seven pillars of aging. Inflammaging is a highly significant risk factor for both morbidity and mortality in the elderly people and in a variety of age-related diseases. Various tissues such as adipose tissue, muscle, brain, and liver have been proposed to play a role in inflammaging, yet the pathway(s) responsible for inflammaging in a tissue or how inflammaging in one tissue can impact other tissues is not known. In the current proposal, we will focus on liver inflammaging. Liver macrophages are the major source of inflammation in the liver and they play a critical role in the pathogenesis of age-related liver diseases, such as NASH. Damage-associated molecular patterns (DAMPs, e.g., HMGB1) are major activators of macrophages and levels of DAMPs increase with age. Necroptosis is a programmed cell death pathway that play a major role in inflammation through the generation of DAMPs. In this proposal we will test the effect of hepatocyte-specific necroptosis on liver inflammation because of the following reasons: (1) Our data show that necroptosis and inflammation increase with age in the liver (and in hepatocytes) of wild type mice that is correlated with chronic liver disease (NASH). Inhibiting necroptosis using necroptosis inhibitor, necrostatin-1s, reduced liver inflammation and NASH. (2) Our data show that necroptosis can affect cell senescence, a pathway associated with aging and inflammation: i.e. inhibiting necroptosis reduced markers of cell senescence in the livers of old mice. (3) There are data showing that inflammation associated with chronic liver disease can cause detrimental effects in other tissues such as brain and skeletal muscle, two key tissues associated with healthspan. Our preliminary studies show that over-expression of MLKL in hepatocytes increases expression of proinflammatory cytokines in the liver and brain of young mice. The central hypothesis of the supplement is that inducing necroptosis in one cell type will affect other cell types in that tissue increasing inflammation in that tissue and will also have cell non-autonomous effects on other tissues. The hypothesis will be tested using a novel knockin mouse model that will allow us to induce necroptosis specifically in hepatocytes by conditionally overexpressing Mlkl, a key gene in necroptosis. Aim 1. To determine the effects of hepatocyte necroptosis on liver; Aim 2. To determine the effect of hepatocyte necroptosis on the secretome; Aim 3. To determine the non-autonomous effects of hepatocyte necroptosis on other tissues.

项目摘要 慢性、低度炎症（炎症）是衰老的标志，也是衰老的七大支柱之一。 炎症是老年人发病率和死亡率的一个非常重要的危险因素， 各种与年龄有关的疾病。各种组织，如脂肪组织、肌肉、脑和肝，已经被植入。 提出在炎症中发挥作用，但负责组织中炎症的途径或如何 一个组织中的炎症会影响其它组织是未知的。在目前的提案中，我们将重点放在肝脏上 发炎肝脏巨噬细胞是肝脏炎症的主要来源，它们在肝脏中起着关键作用 在年龄相关性肝病如NASH的发病机制中。损伤相关分子模式 （DAMP，例如，HMGB 1）是巨噬细胞的主要活化剂，DAMP的水平随年龄增加而增加。 坏死性凋亡是一种程序性细胞死亡途径，在炎症中起主要作用， 的DAMP。在本提案中，我们将测试肝细胞特异性坏死性凋亡对肝脏炎症的影响， 以下原因：（1）我们的数据显示，随着年龄的增长，肝脏坏死性凋亡和炎症增加（和 在肝细胞中）与慢性肝病（NASH）相关。抑制坏死性凋亡， 坏死性凋亡抑制剂necrostatin-1 s，减少肝脏炎症和NASH。(2)我们的数据显示坏死性凋亡 可以影响细胞衰老，这是一种与衰老和炎症相关的途径：即抑制坏死性凋亡减少 老年小鼠肝脏中细胞衰老的标志物。(3)有数据显示， 慢性肝病可能会对其他组织（如大脑和骨骼肌）造成有害影响， 与健康相关的关键组织。我们的初步研究表明，MLKL的过度表达， 肝细胞增加幼鼠肝和脑中促炎细胞因子的表达。中央 该补充剂的假设是在一种细胞类型中诱导坏死性凋亡将影响该组织中的其他细胞类型 增加该组织中的炎症，并且还将对其它组织具有细胞非自主效应。的 我们将使用一种新的敲入小鼠模型来验证这一假设，该模型将使我们能够特异性地诱导坏死性凋亡。 在肝细胞中通过有条件地过表达Mlkl（坏死性凋亡中的关键基因）来表达。目标1.以确定影响 肝细胞坏死;目的2.确定肝细胞坏死对分泌蛋白组的影响; 目标3.确定肝细胞坏死性凋亡对其他组织的非自主性影响。