Genetics to Brain Biomarkers in Kynurenine Pathway Dysfunction

犬尿氨酸通路功能障碍的脑生物标志物的遗传学

基本信息

批准号：
10016396
负责人：
L Elliot Elliot Hong
金额：
$ 76.43万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-09 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10016396
关键词：
Acetylcholine Alleles Award Back Bioinformatics Biological Assay Biological Markers Brain Brain imaging CRISPR/Cas technology Cell model Clinical Cognition Cognitive Cognitive deficits Complement Data Development Diagnosis Disease Dopamine Electrophysiology (science)Enrollment Enzymes Functional disorder Gene Expression Genes Genetic Genetic Predisposition to Disease Genetic Transcription Genetic Variation Genetic study Genotype Glucocorticoids Glutamates Human Immune Immunoblotting Impairment Interferon Type II Knowledge Kynurenic Acid Kynurenine Kynurenine 3-monooxygenase Laboratories Link Measures Mediating Mediation MicroRNAs Modeling Molecular Genetics Mutation Neurons Participant Pathway interactions Patients Peripheral Blood Mononuclear Cell Process Production Proteins Proteomics Reporter Research Personnel Risk Factors Role Sampling Schizophrenia Serotonin Signal Pathway Signal Transduction Stress System Testing Transcriptional Regulation Translating Tryptophan Tryptophan 2,3 Dioxygenase Tryptophanase Variant Work biological adaptation to stress brain circuitry clinical predictors clinical translation cohort design differential expression drug development extracellular vesicles genetic approach genetic variant genome editing glutamatergic signaling insight novel pre-clinical promoter response targeted treatment transcriptome sequencing white matter

项目摘要

Project summary Perturbations in the kynurenine pathway metabolites have been associated with alterations in glutamate, acetylcholine, serotonin and dopamine signaling, and have been linked to schizophrenia. During the first 5 year of the Conte project, we have developed new evidence that kynurenergic effects in schizophrenia maybe dynamically related to stress response and genetics. Identifying the underlying mechanism would be critical to determine whether this pathway is critical in schizophrenia and how it is related to the known pathophysiological glutamate, acetylcholine, serotonin and dopamine signaling in this illness. The downstream substrates of the tryptophan-kynurenine mechanism involve multiple and frequently opposite actions. Although many of these actions have implications in schizophrenia, the field lacks a coherent schizophrenia-kynurenine model, hindering meaningful preclinical-clinical translations. The difficulty may be due to the inherent complexity of the system and its interactions with genetics and developmental risk factors. We will employ a combination of cellular to patient ex-vivo cellular genetic approaches to analyze the role genetic effects on the kynurenine pathway signaling in schizophrenia. The empahsis is on stress-induced kynurenergic response and its associated brain circuitry and glutamatergic signaling biomarkers. The project is ambitious and translational, involving clinical, brain imaging, and cellular models for specific genetic effects. However, we have formed a strong, highly integrated team and project design, and the preliminary studies support our proposed specific aims, demonstrate feasibility, and suggest a significant potential for novel discoveries if these aims are supported in the proposed studies. Knowledge on how the kynurenine pathway is involved in clinical schizophrenia patients will lead to more specific and better treatment targets for drug development.

项目摘要 Kynurenine途径代谢产物中的扰动与谷氨酸的改变有关，乙酰胆碱，5-羟色胺和多巴胺信号传导，并与精神分裂症有关。在前5年在孔戴项目中，我们已经开发了新的证据，表明精神分裂症中的kynureneragic效果可能与压力反应和遗传学动态有关。确定基本机制对于确定该途径在精神分裂症中是否至关重要及其与已知的相关性病理生理生理学谷氨酸，乙酰胆碱，5-羟色胺和多巴胺信号在这种疾病中。下游色氨酸 - 京素氨酸机制的底物涉及多种和经常相反的作用。虽然这些动作中有许多在精神分裂症中具有影响，该领域缺乏连贯的精神分裂症 - 京素氨酸模型，阻碍有意义的临床前临床翻译。困难可能是由于固有的系统的复杂性及其与遗传学和发育风险因素的相互作用。我们将采用一个细胞与患者前体细胞遗传方法的结合，分析遗传对遗传作用的作用精神分裂症中的Kynurenine途径信号传导。 empahsis正在应激引起的kynureneragic反应和它相关的脑电路和谷氨酸能信号生物标志物。该项目是雄心勃勃的，翻译的，涉及特定遗传作用的临床，脑成像和细胞模型。但是，我们已经形成了强大，高度集成的团队和项目设计，初步研究支持我们提出的特定目的，证明可行性并提出了新发现的重要潜力，如果这些目标是在拟议的研究中得到支持。关于kynurenine途径如何参与临床的知识精神分裂症患者将为药物开发带来更具体，更好的治疗靶标。