Role of Kynurenine System on Brain Inflammatory Responses in the Offspring of Immune Challenged Rats

犬尿氨酸系统对免疫缺陷大鼠后代脑炎症反应的作用

基本信息

批准号：
8847403
负责人：
Leonardo H Tonelli
金额：
$ 36.67万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8847403
关键词：
Adolescence Adolescent Adopted Adult Amino Acids Animal Model Animals Area Autistic Disorder Bacterial Infections Behavioral Blood Brain Cerebral cortex Cognitive Cognitive deficits Development Disease Embryo Enzymes Exposure to Grant Hour Immune Immune response Immune system Impaired cognition Infection Inflammatory Response Injection of therapeutic agent Instruction Kynurenic Acid Kynurenine Lead Life Mediator of activation protein Microglia Modeling Molecular Mothers Mus Neurodevelopmental Disorder Neurons Outcome Pathology Pathway interactions Patients Performance Peripheral Placenta Poly I-C Pregnancy Process Production Property Rattus Research Risk Factors Rodent Model Role Schizophrenia Series Staging Stress System Testing Time Tissues Tryptophan Tryptophan 2,3 Dioxygenase Viral Virus Diseases Work base behavior test behavioral response cognitive function cognitive performance cytokine fetal immune activation improved inhibitor/antagonist killings kynurenine aminotransferase II macrophage mimetics morris water maze neurobehavioral neurochemistry new therapeutic target novel object recognition offspring pathogen postnatal pregnant prenatal prevent psychological stressor pup response social social stress stressor viral RNA

项目摘要

Complications due to infections during pregnancy are a significant risk factor for the emergence of schizophrenia (SZ) in the offspring. Animal models of prenatal immune challenge provide support for the idea that developmental immune abnormalities promote specific vulnerabilities of the disease. Conversion of the amino acid tryptophan to kynurenine (KYN) and its associated metabolites (collectively referred to as kynurenines) is one ofthe mechanisms activated during viral and bacterial infections. In particular, kynurenic acid (KYNA) is known to have neuroactive properties and is also elevated in the cerebral cortex of SZ patients. The purpose ofthe present project is to evaluate the involvement ofthe kynurenine system in the established animal model of prenatal infection. The central hypothesis is that activation ofthe enzyme indoleamine 2,3-dioxygenase (IDO) in response to the viral RNA mimetic poly l:C in the mother leads to increased production of kynurenines, including KYNA in the brain of embryos. This increase in KYNA will in turn be responsible for promoting microglia to adopt an alternative activated state also known as M2 activation. It is further hypothesized that this shift in activation state will be maintained throughout development, at least in a proportion of microglia, and that it will be exacerbated in response to stressors resulting in enhanced production of KYNA in the brain. In concert with the central hypothesis ofthe center grant, an increase in KYNA levels in the brain is believed to be responsible for cognitive impairments. We will test these hypotheses using rats prenatally challenged with poly l:C and subjected to a series of studies including a) documenting the trajectory of changes in the kynurenine pathway during pre and post- natal brain development and in relation to microglia activation; b) evaluating peripheral and central kynurenines and microglial responses to social stressors during peri-adolescence; and c) testing whether timed KAT II inhibition (reduction of KYNA production) prevents and/or reverses the neurobehavioral deficits seen in peri- adolescents. The present project will also involve the study of peripheral and placental cytokine and kynurenine responses in the mothers, as well as peripheral and central immune responses in the offspring.

妊娠期间感染引起的并发症是出现妊娠期感染的重要危险因素后代患有精神分裂症（SZ）。产前免疫挑战的动物模型为认为发育性免疫异常会促进该疾病的特定脆弱性。转换为色氨酸至犬尿氨酸 (KYN) 及其相关代谢物（统称为犬尿氨酸）是病毒和细菌感染期间激活的机制之一。特别是犬尿症已知酸 (KYNA) 具有神经活性特性，并且在 SZ 的大脑皮层中含量也升高患者。本项目的目的是评估犬尿氨酸系统在建立产前感染动物模型。中心假设是酶的激活吲哚胺 2,3-双加氧酶 (IDO) 响应母亲体内的病毒 RNA 模拟物 Poly L:C，导致增加了犬尿氨酸的产生，包括胚胎大脑中的 KYNA。 KYNA 的增加将负责促进小胶质细胞采取另一种激活状态，也称为 M2 激活。进一步假设激活状态的这种转变将在整个过程中保持发育，至少在一定比例的小胶质细胞中，并且会因应激源而加剧导致大脑中 KYNA 的产生增强。与中心的中心假设一致 Grant 认为，大脑中 KYNA 水平的增加被认为是导致认知障碍的原因。我们将使用产前接受 Poly L:C 攻击的大鼠并进行一系列研究来测试这些假设包括 a) 记录产前和产后犬尿氨酸途径的变化轨迹大脑发育及其与小胶质细胞激活的关系； b) 评估外周和中枢犬尿氨酸以及青春期期间小胶质细胞对社会压力的反应； c) 测试是否定时 KAT II 抑制（减少 KYNA 产生）可预防和/或逆转围周期出现的神经行为缺陷青少年。本项目还将涉及外周和胎盘细胞因子的研究母亲的犬尿氨酸反应，以及后代的外周和中枢免疫反应。