Toxoplasma gondii Regulation of Host GABAergic Signaling

弓形虫对宿主 GABA 信号传导的调节

• 批准号: 9212770
• 负责人: Ira J Blader
• 金额: $ 55.3万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9212770
• 关键词: Acquired Immunodeficiency Syndrome; Address; Affect; Antibodies; Architecture; Astrocytes; Blood - brain barrier anatomy; Brain; Cancer Patient; Cells; Communicable Diseases; Complication; Data; Defect; Disease; Electron Microscopy; Elements; Encephalitis; Encephalopathies; Enzymes; Epilepsy; Exhibits; Fetus; Functional disorder; Genes; Genetic; Genetic Screening; Glutamates; Goals; Growth; Health; Homeostasis; Hypersensitivity; Immune; Immune response; Immunocompromised Host; Immunohistochemistry; Immunology; Impairment; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Inhibitory Synapse; Interneurons; Label; Life; Link; Maintenance; Mediating; Messenger RNA; Microglia; Molecular; Morphology; Mus; Neuraxis; Neurologic; Neurons; Neurosciences; Parasite Control; Parasites; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pharmacology; Phenotype; Population; Predisposition; Presynaptic Terminals; Proteins; Quantitative Trait Loci; Regulation; Reporter; Role; Seizures; Signal Transduction; Site; Structure; Symptoms; Synapses; Testing; Tissues; Toxoplasma; Toxoplasma gondii; Toxoplasmosis; Work; base; cytokine; gamma-Aminobutyric Acid; genetic approach; immune function; in utero; inhibitory neuron; mouse model; neural circuit; neuronal circuitry; neurotransmission; novel therapeutics; presynaptic; public health relevance; therapy development

 DESCRIPTION (provided by applicant): Seizures are a common and life-threatening complication of individuals suffering from infections and inflammation in the central nervous system. In these individuals, seizures develop due to a variety of reasons including breakdown of the blood-brain barrier, changes in ionic homeostasis, and/or increased abundance of inflammatory proteins such as cytokines and antibodies. But, how these changes in the brain alter synaptic wiring and neurotransmission that cause epileptiform activity is largely unknown. The protozoan parasite Toxoplasma gondii infects approximately one-third of the world's population. Most people are asymptomatic because the parasite resides latently within brain and other tissues. But individuals who are immunocompromised or are infected in utero develop toxoplasmosis when the parasite reactivates and the host immune response is unable to control parasite replication or is dysregulated leading immune-mediated tissue destruction. If reactivation occurs in the brain, the resulting toxoplasmic encephalitis presents with a variety of neurological sequelae that includes seizures. Using a murine model for toxoplasmic encephalitis our data indicates that Toxoplasma specifically alters the distribution of key proteins that localie to GABAergic synapses. This change in GABAergic synaptic connectivity causes the mice to develop seizures because these synapses are critical for controlling the flow and timing of information transfer in the brain. This work will define how these proteins are mislocalized (Aim 1), determine the role of inflammatory cells in GABAergic protein mislocalization (Aim 2), and identify the parasite factors that affect GABAergic protein localization and onset of seizures (Aim3). The long-term goal of this work is to determine how seizures develop in Toxoplasma-infected individuals and use this information to generate novel therapies to treat these patients and others suffering from infection-induced seizures.

 描述（由申请人提供）：癫痫发作是中枢神经系统感染和炎症患者常见且危及生命的并发症。在这些个体中，癫痫发作的原因有多种，包括血脑屏障的破坏、离子稳态的变化和/或炎症蛋白（如细胞因子和抗体）丰度的增加。但是，大脑中的这些变化如何改变导致癫痫样活动的突触接线和神经传递，目前尚不清楚。原生动物寄生虫弓形虫感染了世界上大约三分之一的人口。大多数人没有症状，因为寄生虫潜伏在大脑和其他组织内。但是，当寄生虫重新激活并且宿主免疫反应无法控制寄生虫复制或失调导致免疫介导的组织破坏时，免疫功能低下或在子宫内感染的个体就会患上弓形体病。如果大脑中发生重新激活，由此产生的弓形虫脑炎会出现多种症状 神经系统后遗症，包括癫痫发作。使用弓形虫脑炎小鼠模型，我们的数据表明弓形虫特异性地改变位于 GABA 能突触的关键蛋白质的分布。 GABA 能突触连接的这种变化会导致小鼠癫痫发作，因为这些突触对于控制大脑中信息传输的流动和时间至关重要。这项工作将定义这些蛋白质如何错误定位（目标 1），确定炎症细胞在 GABA 能蛋白质错误定位中的作用（目标 2），并确定影响 GABA 能蛋白质定位和癫痫发作的寄生虫因素（目标 3）。这项工作的长期目标是确定弓形虫感染者的癫痫发作是如何发生的，并利用这些信息来开发新的疗法来治疗这些患者和其他患有感染引起的癫痫发作的患者。