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

• 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
• 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

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并发症的一个重要风险因素。 精神分裂症（SZ）的后代。产前免疫攻击的动物模型为免疫治疗提供了支持。 认为发育性免疫异常促进了疾病的特定脆弱性。转化 氨基酸色氨酸转化为犬尿氨酸（KYN）及其相关代谢物（统称为 犬尿氨酸）是在病毒和细菌感染期间激活的机制之一。特别是犬尿氨酸 已知KYNA具有神经活性，并且在SZ的大脑皮层中也升高 患者本项目的目的是评估犬尿氨酸系统参与 建立产前感染动物模型。核心假设是酶的激活 吲哚胺2，3-双加氧酶（IDO）对母体中病毒RNA模拟物poly I：C的应答导致 增加犬尿氨酸的产生，包括胚胎大脑中的KYNA。KYNA的增加将在 反过来负责促进小胶质细胞采取另一种激活状态，也称为M2 activation.进一步假设，激活状态的这种转变将在整个过程中保持。 至少在一定比例的小胶质细胞中，这种情况会因压力源而加剧 导致大脑中KYNA的产生增加。与中心的中心假设一致 授予，增加KYNA水平在大脑中被认为是负责认知障碍.我们将 使用产前用聚乳酸激发的大鼠来检验这些假设，并进行一系列研究 包括a）记录出生前和出生后犬尿氨酸途径的变化轨迹 脑发育和与小胶质细胞活化的关系; B）评价外周和中枢犬尿氨酸 和小胶质细胞对青春期前后社会压力的反应;以及c）测试是否定时KAT II 抑制（减少KYNA的产生）可以预防和/或逆转神经行为缺陷， 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。