Nutritional Components of Psychiatric Disease and Treatment Response

描述（由申请人提供）：通过本申请中提出的研究和培训，我将在分子和细胞生物学以及情绪障碍神经生物学研究方面的正规教育的基础上，发展了解精神疾病饮食成分的罕见专业知识。有充分的基础科学证据表明，饮食和营养影响大脑功能和精神疾病。然而，由于相对缺乏系统的临床研究，精神科医生很少在临床上探讨营养问题。我的目标是利用K 01奖来发展饮食因素在情绪和代谢之间的界面作用的转化研究专业知识。该应用程序的培训部分包括代谢组学科学，双相情感障碍，遗传学和生物统计学的临床研究的指导培训;以及人类营养科学，生物统计学和人类研究伦理学的教学培训。本申请的研究部分侧重于关于必需脂肪酸在双相情感障碍中的作用的特定假设，并整合了指导和教学培训的各个方面。先前的研究表明多不饱和脂肪酸（PUFA）与双相情感障碍有关。低组织浓度的omega-3脂肪酸与双相情感障碍有关，几项研究表明，补充omega-3脂肪酸可能对治疗这种疾病有效。然而，这些数据是混淆的，因为omega-3与omega-6的组织比例也很重要，因为这两类PUFA相互竞争，并发挥许多相反的生理作用。它们的组织浓度在很大程度上反映了饮食，然而，调节脂质代谢的基因中的等位基因变异也参与其中。因此，在PUFA谱的控制中存在基因相互作用的饮食。有趣的是，一种用于治疗双相情感障碍的情绪稳定剂药物的作用机制是特异性抑制神经元中ω-6，花生四烯酸的周转和下游信号传导。先前评估omega-3治疗双相情感障碍的疗效的研究，以及正在使用的情绪稳定剂，没有考虑到与omega-6活性相关的饮食或遗传因素。因此，这代表了临床研究的新途径。高omega-6组织水平，特别是花生四烯酸的水平，可能会对抗omega-3补充剂或情绪稳定剂治疗方法的功效，但尚未对此进行评估。通过拟议的研究，我们将评估控制PUFA谱的饮食和遗传变异对双相情感障碍病因学和治疗抗性的贡献。凭借目前的奖项，我将在人类营养，代谢组学和临床精神病学研究方面进行培训，并将培训应用于测试双相情感障碍中基因相互作用的特定饮食作用的假设。我将从这次培训中脱颖而出，成为一名有竞争力的临床研究人员，该领域具有通过了解影响心理健康和疾病的复杂饮食因素来影响当前精神病学实践的重大潜力。

DESCRIPTION (provided by applicant): With the research and training proposed in this application, I will build on my formal education in molecular and cellular biology and research in the neurobiology of mood disorders, to develop rare expertise understanding dietary components of mental illness. There is ample basic science evidence that diet and nutrition influence brain function and psychiatric illness. However, psychiatrists rarely explore nutritional issues in the clinic due to the relative lack of systematic clinical research. I aim to use the K01 award to develop translational research expertise in the role of dietary factors at the interface between mood and metabolism. The training component of this application includes mentored training in metabolomic sciences, clinical research in bipolar disorder, genetics, and biostatistics; as well as didactic training in human nutrition science, biostatistics, and the ethics of human research. The research component of this application focuses on a specific hypothesis regarding the role of essential fatty acids in bipolar disorder and integrates all aspects of the mentored and didactic training. Previous research implicates polyunsaturated fatty acids (PUFA) in bipolar disorder. Low tissue concentrations of omega-3 fatty acids associate with bipolar disorder, and several studies show that supplementing omega-3s may be efficacious in treating the disease. However, the data are confounded because the tissue ratio of omega-3s to omega-6s is also important, since these two classes of PUFA compete with each other and play many opposing physiological roles. Their tissue concentrations largely reflect the diet, however, allelic variation in genes that regulate lipid metabolism are also involved. Therefore, there is a diet by gene interaction in the control of PUFA profiles. Interestingly, one proposed mechanism of action for mood stabilizer medications used to treat bipolar disorder is the specific inhibition of turnover and downstream signaling of the omega-6, arachidonic acid, in neurons. Previous studies evaluating the efficacy of omega-3s in treating bipolar disorder, and on-going use of mood stabilizers, have not taken dietary or genetic factors relative to omega-6 activity into account. Therefore, this represents a new avenue for clinical research. High omega-6 tissue levels, especially those of arachidonic acid, may oppose the efficacy of omega-3 supplementation or mood stabilizer treatment approaches, yet this has not been evaluated. With the proposed research, we will evaluate the contribution of diet and genetic variants controlling PUFA profiles, to bipolar disorder etiology and treatment resistance. With the current award, I will train in human nutrition, metabolomics and clinical psychiatric research and apply the training to test a hypothesis for the role of a specific diet by gene interaction in bipolar disorder. I will emerge from this training as a competitive clinical researcher in a field that has a significant potential to impact current psychiatric practice by understanding complex dietary factors that influence mental health and disease.