Genetics to Brain Biomarkers in Kynurenine Pathway Dysfunction

项目总结 犬尿氨酸途径代谢产物的扰动与谷氨酸的变化有关， 乙酰胆碱、5-羟色胺和多巴胺信号，并与精神分裂症有关。在前5年 在CONTE项目中，我们发现了新的证据，即运动神经能在精神分裂症中的作用可能 与应激反应和遗传学有动态联系。确定潜在的机制对于 确定这一途径是否对精神分裂症至关重要，以及它与已知的 谷氨酸、乙酰胆碱、5-羟色胺和多巴胺在本病中的病理生理信号。下游 色氨酸-犬尿氨酸机制的底物涉及多个经常相反的作用。虽然 这些行为中的许多都对精神分裂症有影响，该领域缺乏一种连贯的精神分裂症-犬尿氨酸 模型，阻碍了有意义的临床前-临床转换。困难可能是由于固有的 系统的复杂性及其与遗传和发育风险因素的相互作用。我们将聘请一名 结合细胞与患者体外细胞遗传学方法来分析遗传效应对 犬尿氨酸通路在精神分裂症中的信号转导。这种增强作用是关于应激诱导的肌动能反应和 其相关的脑回路和谷氨酸能信号生物标志物。该项目雄心勃勃，具有翻译性， 涉及特定遗传效应的临床、脑成像和细胞模型。然而，我们已经形成了一个 强大、高度集成的团队和项目设计，以及初步研究支持我们提议的具体 目标，证明可行性，并建议新发现的巨大潜力，如果这些目标是 在拟议的研究中得到支持。犬尿氨酸途径如何参与临床的认识 精神分裂症患者的药物开发将导致更具体、更好的治疗靶点。

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.