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.

由于怀孕期间感染引起的并发症是出现的重要危险因素 后代的精神分裂症（SZ）。产前免疫挑战的动物模型为 发育免疫异常的想法会促进该疾病的特定漏洞。转换 氨基酸色氨酸至kynurenine（Kyn）及其相关的代谢物（统称为 Kynurenines）是在病毒和细菌感染过程中激活的机制之一。特别是kynurenic 已知酸（Kyna）具有神经活性特性，并且在SZ的大脑皮层中也升高 患者。本项目的目的是评估kynurenine系统参与 建立的产前感染动物模型。中心假设是酶的激活 吲哚胺2,3-二氧酶（IDO）响应于母亲的病毒RNA模拟poly l：C导致 增加的kynurenines的产生，包括胚胎大脑中的Kyna。 Kyna的这种增加将在 转弯负责促进小胶质细胞采用替代激活状态，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 至少在小胶质细胞中开发，并且会因压力源而加剧 导致大脑中的Kyna产生增强。与中心的中心假设一致 格兰特（Grant），据信大脑中的Kyna水平增加是造成认知障碍的原因。我们将 使用由Poly L：C挑战并进行一系列研究的大鼠测试这些假设 包括a）记录前后新生尿素途径变化的轨迹 大脑发育和小胶质细胞激活； b）评估外围和中央kynurenines 在青春期期间对社会压力源的小胶质反应； c）测试是否定时KAT II 抑制（减少Kyna产生）可防止和/或逆转神经行为缺陷 青少年。本项目还将涉及周围和胎盘细胞因子的研究以及 母亲中的Kynurenine反应，后代的外围和中央免疫反应。