Environmental and Mutant Huntingtin-mediated Upregulation of Indoleamine-2,3-dioxygenase in Huntington's Disease Pathogenesis

亨廷顿病发病机制中环境和突变亨廷顿介导的吲哚胺-2,3-双加氧酶上调

• 批准号: 9552295
• 负责人: Jonathan H Fox
• 金额: $ 35.33万
• 依托单位: UNIVERSITY OF WYOMING
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-25 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9552295
• 关键词: Address; Affect; Aging-Related Process; Behavior; Brain; Brain Diseases; CAG repeat; CD8-Positive T-Lymphocytes; Catabolism; Central Nervous System Diseases; Central Nervous System Infections; Cessation of life; Chemosensitization; Clinical; Clinical Trials Design; Data; Dioxygenases; Disease; Disease Progression; Drug Targeting; Enzymes; Functional disorder; Gatekeeping; Genes; Genetic Crosses; Genetic Transcription; Goals; Herpes Simplex Infections; Human; Huntington Disease; Huntington gene; Immune System Diseases; Immune System and Related Disorders; Infection; Infection prevention; Inflammatory; Kynurenine; Lead; Length; Link; Measures; Mediating; Mental disorders; MicroRNAs; Microglia; Mus; Mutation; Neurodegenerative Disorders; Onset of illness; Outcome; Oxidative Stress; Parasites; Pathogenesis; Pathway interactions; Patients; Peripheral; Permeability; Premature Mortality; Regulation; Role; Signal Pathway; Stimulus; T-Lymphocyte; Testing; Time; Toxoplasma gondii; Toxoplasmosis; Tryptophan; United States National Institutes of Health; Up-Regulation; adaptive immune response; brain morphology; disease phenotype; drug discovery; early onset; effective therapy; improved; indoleamine; inhibitor/antagonist; knock-down; latent infection; monocyte; mutant; pathogen; polyglutamine; premature; research study; response; therapeutic development

Project Summary: The primary goal of this project is to test our core hypothesis that upregulation of activity of kynurenine pathway gatekeeper indoleamine-2, 3-dioxygenase potentiates Huntington’s disease (HD) onset and progression. HD is an ultimately fatal neurodegenerative disease that afflicts about 30000 people in the USA alone and has no effective treatments. CAG-repeat expansion within the huntingtin gene results in expression of a polyglutamine-expanded mutant huntingtin protein (mhtt) leading to downstream effects including transcriptional dysregulation, oxidative stress and activation of the kynurenine pathway of tryptophan degradation. There is growing evidence that disruption of the kynurenine pathway (KP) contributes to the pathogenesis of HD as well as other neurodegenerative and psychiatric disorders. However, little is known about the role of indoleamine-2, 3-dioxygenase (IDO), the enzyme that catalyzes the first and rate-limiting step. We show for the first time large increases in IDO activity in mouse HD brain suggesting that IDO is central to pathway regulation. Others have shown that common latent neuroinvasive pathogens Toxoplasma gondii (T. gondii) and herpes simplex 1 (HSV1) upregulate brain IDO suggesting that they may potentiate HD. We show for the first time that T. gondii-infected HD mice have significant disease potentiation with early brain IDO activation, premature mortality, higher brain parasite burden and dysfunctional T- lymphocyte responses. These important findings point to a link between HD, IDO and IDO-activating CNS infections. Aim 1 will test the hypothesis that decreasing IDO activity is protective in pathogen-free HD mice. In the three sub-aims we will determine the effect of global, brain microglial and peripheral IDO inhibition on a broad range of outcomes in HD mice. Aim 2 will test the hypothesis that latent T. gondii infection potentiates HD and upregulates IDO. Aim 2A will test the effect of latent T. gondii infection in HD mice expressing full- length mhtt. Aim 2B we will determine using human brain if T. gondii infection correlates with earlier onset or faster progression of HD. Aim 3 will test the hypothesis that mhtt-induced immune dysfunction is mediated by IDO / KP and also results in a dysfunctional response to HSV1. Aim 3A will determine if IDO / KP activation mediates T-lymphocyte dysfunction and premature mortality in T. gondii-infected HD mice. Aim 3B will evaluate the effect of latent HSV1 in HD mice and will also determine if HSV1 infection in human HD correlates with earlier disease onset and faster progression. Together, the studies will determine the extent to which IDO contributes to HD, how common neuroinfections that upregulate IDO affect the course of HD, and the mechanisms involved. Findings will be relevant to therapeutic development, understanding the large variability in human HD, improving clinical trial design, and also to other CNS diseases in which the kynurenine pathway is implicated.

项目总结：本项目的主要目标是验证我们的核心假设，即