Genetics to Brain Biomarkers in Kynurenine Pathway Dysfunction

项目概要 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传导，并与精神分裂症有关。第一个 5 年期间 在 Conte 项目中，我们开发了新的证据，表明犬尿能对精神分裂症的影响可能 与应激反应和遗传动态相关。确定潜在的机制对于 确定该途径在精神分裂症中是否至关重要以及它与已知的相关性如何 这种疾病中的病理生理谷氨酸、乙酰胆碱、血清素和多巴胺信号传导。下游 色氨酸-犬尿氨酸机制的底物涉及多种且经常相反的作用。虽然 其中许多行为对精神分裂症有影响，该领域缺乏连贯的精神分裂症-犬尿氨酸 模型，阻碍了有意义的临床前-临床转化。困难可能是由于其固有的 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 结合细胞与患者离体细胞遗传学方法来分析遗传效应对患者的影响 精神分裂症中的犬尿氨酸通路信号传导。重点是压力引起的犬尿能反应和 其相关的大脑回路和谷氨酸信号生物标志物。该项目雄心勃勃且具有转化性， 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、高度整合的团队和项目设计，初步研究支持我们提出的具体方案 目标，证明可行性，并提出新发现的巨大潜力（如果这些目标是的话） 在拟议的研究中得到支持。关于犬尿氨酸途径如何参与临床的知识 精神分裂症患者的研究将为药物开发带来更具体、更好的治疗目标。

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.