Genetics to Brain Biomarkers in Kynurenine Pathway Dysfunction

项目摘要 犬尿氨酸途径代谢物的扰动与谷氨酸的改变有关， 乙酰胆碱，血清素和多巴胺信号，并已与精神分裂症。在第一个5年 在Conte项目中，我们已经发现了新的证据，表明精神分裂症中的犬尿氨酸能效应可能 与压力反应和遗传学有着密切的关系。确定潜在的机制对于 确定这一途径是否在精神分裂症中至关重要，以及它与已知的 病理生理谷氨酸，乙酰胆碱，血清素和多巴胺信号在这种疾病。下游 Dahan-kynurenine机制的底物涉及多种且经常相反的作用。虽然 许多这些行动的影响，精神分裂症，该领域缺乏一个连贯的精神分裂症-犬尿氨酸 模式，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和发育风险因素的相互作用。我们将雇用一名 细胞与患者离体细胞遗传学方法的组合，以分析基因作用对细胞的影响。 犬尿氨酸信号通路在精神分裂症中的作用重点是应激诱导的犬尿素能反应， 其相关的脑回路和神经元能信号生物标志物。该项目是雄心勃勃的和翻译， 涉及临床、脑成像和特定遗传效应的细胞模型。然而，我们已经形成了一个 强大的，高度整合的团队和项目设计，以及初步研究支持我们提出的具体 目标，证明可行性，并提出新发现的重大潜力，如果这些目标是 在拟议的研究中得到支持。了解犬尿氨酸途径如何参与临床 精神分裂症患者将导致更具体和更好的治疗药物开发的目标。

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.