Immune-based nutrient deprivation and neurodegenerative disease

基于免疫的营养剥夺和神经退行性疾病

基本信息

批准号：
9280800
负责人：
CAROL Anne COLTON
金额：
$ 41.67万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-15 至 2020-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9280800
关键词：
Abeta synthesis Acute Address Age Alzheimer&apos s Disease Alzheimer&apos s disease model Amino Acids Amyloid Amyloid beta-Protein Amyloid deposition Anti-Inflammatory Agents Anti-inflammatory Antigens Apoptosis Arginine Astrocytes Autophagocytosis Bacterial Infections Behavioral Blood Bone Marrow Brain Brain Diseases Brain region Cell Death Cells Chimera organism Chronic Data Deposition Diet Dioxygenases Disease Disease Progression Environment Enzymes Essential Amino Acids Event Failure Flow Cytometry Gene Expression Gene Proteins Genes ITGAX gene Immune Immune system Immunosuppression Immunosuppressive Agents Infection Inflammation Mediators Inflammatory Interleukin-1 Knock-out Label Lead Measures Mediating Microarray Analysis Microglia Mouse Strains Mus NOS2A gene Nerve Degeneration Neurodegenerative Disorders Neurons Nitrogen Nutrient Ornithine Oxygen Pathology Pathway interactions Peptides Play Polyamines Population Process Production Proline Protein Isoforms Research Proposals Role Severities Signal Transduction Source Starvation System Testing Time Tissues Tryptophan Virus Diseases arginase base biological adaptation to stress brain parenchyma extracellular gene repair immunotoxicity indoleamine killings mRNA Expression macrophage metabolomics mouse model neuron loss novel novel strategies nutrient deprivation pathogen protein expression public health relevance response tau Proteins uptake

项目摘要

DESCRIPTION (provided by applicant): The role of the immune system in neuronal death in chronic neurodegenerative diseases remains a critical unsolved question. One common view is that chronic neurodegeneration represents a form of immune pathology, in which the excessive production of inflammatory mediators such as TNFalpha, IL-1beta, and reactive nitrogen or oxygen species leads to neuronal cell death. There is a strong precedent for such immune pathology in diseases such as acute viral or bacterial infection. However new evidence from multiple sources argues that pro- inflammatory immune pathology is not the cause of neuronal loss in chronic brain disease. Here we propose that a different type of immune pathology, one most commonly associated with immune suppression, is responsible for neuronal cell death in chronic neurodegenerative diseases such as Alzheimer's disease. Immunosuppression is a feature of acquired immune privilege that protects critical cells but reduces the ability of the tissue to mount an effective toxic response that would "clear" immunogens including Abeta. Ineffectual clearance leads to "persistent infection" and hence to a chronic inflammatory disease. Our data on a mouse model of AD that shows full AD-like pathology (the CVN mouse) strongly suggest that Alzheimer's disease may represent an inappropriate immunosuppressive state, initiated or facilitated by Abeta production. Preliminary data from this mouse show increased expression of anti- inflammatory/repair genes and proteins at the onset of cellular Abeta production and parenchymal deposition. Pro-inflammatory gene expression occurs with age but is accompanied by increased expression of anti-inflammatory and tolerogenic genes and proteins. Thus, we believe that an immunosuppressive environment is maintained throughout the neurodegenerative process. Nutrient deprivation is a principal mechanism by which immune cells induce immune- suppression. By increasing arginine and tryptophan uptake, immune cells reduce the levels of these essential amino acids in the microenvironment. Surrounding cells may undergo amino acid starvation and increased autophagy leading to cell death. Our preliminary data suggest that amino acid starvation occurs in CVN mice brain. Increased activity of two enzymes are featured in immunosuppression; namely arginase (Arg) that uses arginine to make ornithine for polyamine and proline production and Indoleamine dioxygenase (IDO) that uses tryptophan to produce kyneurine. The CVN mouse model of AD demonstrates both decreased brain levels of arginine and increased arginase and IDO expression. This proposal will focus on the role of nutrient deprivation as a key factor in the induction of autophagy and neuronal loss in AD. The aims will establish, 1) the relationship between nutrient deprivation and the progression of AD- like pathology in the CVN mouse 2) if immunosuppressive immune cells contribute directly to disease progression through regional nutrient deprivation and 3) if immune-mediated nutrient deprivation plays a causal role in neuronal death and AD pathology. These proposed studies represent a novel approach to understanding the basic mechanisms of immune mediated disease in chronic neurodegenerative disease.

描述（由申请人提供）：免疫系统在慢性神经退行性疾病中神经元死亡中的作用仍然是一个尚未解决的关键问题。一种常见的观点认为，慢性神经退行性病变代表一种免疫病理学形式，其中炎症介质（如 TNFα、IL-1β 和活性氮或氧物质）的过量产生导致神经元细胞死亡。在急性病毒或细菌感染等疾病中存在这种免疫病理学的先例。然而，来自多个来源的新证据表明，促炎性免疫病理学并不是慢性脑病中神经元损失的原因。在这里，我们提出一种不同类型的免疫病理学，一种最常与免疫抑制相关的免疫病理学，是导致阿尔茨海默病等慢性神经退行性疾病中神经元细胞死亡的原因。免疫抑制是获得性免疫特权的一个特征，它可以保护关键细胞，但会降低组织产生有效毒性反应的能力，从而“清除”包括 Abeta 在内的免疫原。无效的清除会导致“持续感染”，从而导致慢性炎症性疾病。我们对显示出完全类似 AD 病理学的 AD 小鼠模型（CVN 小鼠）的数据强烈表明，阿尔茨海默病可能代表一种不适当的免疫抑制状态，由 Abeta 的产生引发或促进。该小鼠的初步数据显示，在细胞 Abeta 产生和实质沉积开始时，抗炎/修复基因和蛋白质的表达增加。促炎基因表达随着年龄的增长而发生，但伴随着抗炎和耐受基因和蛋白质的表达增加。因此，我们相信在整个神经退行性过程中维持免疫抑制环境。营养剥夺是免疫细胞诱导免疫抑制的主要机制。通过增加精氨酸和色氨酸的摄取，免疫细胞降低微环境中这些必需氨基酸的水平。周围细胞可能会经历氨基酸饥饿和自噬增加，导致细胞死亡。我们的初步数据表明，CVN 小鼠大脑中发生氨基酸饥饿。两种酶的活性增加是免疫抑制的特征；即精氨酸酶（Arg）和吲哚胺双加氧酶（IDO），精氨酸酶使用精氨酸产生鸟氨酸以生产多胺和脯氨酸，吲哚胺双加氧酶（IDO）使用色氨酸产生犬神经氨酸。 AD 的 CVN 小鼠模型表明，大脑精氨酸水平降低，精氨酸酶和 IDO 表达增加。该提案将重点关注营养剥夺作为 AD 中诱导自噬和神经元损失的关键因素的作用。目标将确定：1) CVN 小鼠营养剥夺与 AD 样病理进展之间的关系；2) 免疫抑制性免疫细胞是否通过局部营养剥夺直接促进疾病进展；3) 免疫介导的营养剥夺是否在疾病进展中发挥作用。神经元死亡和 AD 病理学中的因果作用。这些拟议的研究代表了一种了解慢性神经退行性疾病中免疫介导疾病基本机制的新方法。