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.

妊娠期感染引起的并发症是出现妊娠期感染的重要危险因素