Gene Expression to Expand Knowledge of Inflammatory Depression

描述（由申请人提供）：K23辅导职业发展奖的提案描述了一项培训和研究计划，该计划将为申请人Marisa Toups MD的职业生涯做好准备，作为一名独立的研究者，开发基于基因表达的免疫功能障碍生物标志物，促进抑郁症的个性化护理。申请人在基础免疫学研究、临床培训和成功生产率记录方面的背景特别适合本提案，以解决致力于理解和推进情绪障碍治疗的临床科学家的需求。为了成功的职业发展，已经创建了一个全面的培训和研究计划-基因表达以扩大炎症性抑郁症的知识（GEEK-ID）项目-与Madhukar Trivedi博士和Robert Danzter博士DVM博士，博士，他们作为应用程序的主要导师。GEEK-ID项目的培训部分有两个主要目标。目的1是培养独立研究者成功进行生物标志物临床验证所需的技能，用于个性化护理。这一目标建立了实践技能和培训将集中在全基因组基因表达作为一种实验方法。目标1的培训包括三个方面：1）选择适当的研究设计和生物标志物试验的统计数据; 2）成功管理临床操作和数据收集; 3）适当收集、处理、储存和选择高质量生物学数据的分析方法。目的2是了解免疫系统在情绪障碍中的功能作用，以及它如何在免疫基因表达中表现出来。培训将提供基础知识，作为目标1中所学技能的基础。该培训涉及三个领域的理解：1）先天免疫机制2）大脑和免疫系统之间的通信机制和3）免疫系统中基因表达调控的知识。拟议的研究旨在识别和表征一种具有先天免疫激活特征的抑郁症机制上不同的亚型。在横断面设计中，将对100名MDD成人进行临床表型分析，并将血液RNA测序比较高C反应蛋白（CRP）和低CRP受试者。据推测，CRP相关基因的表达模式将匹配的动物和人类模型的先天免疫激活，应激反应，和情绪障碍。所涉及的途径是丝裂原活化蛋白激酶（MAPK）信号传导途径、转录因子核因子- κ B（NF- κ B）和环腺苷酸反应元件结合蛋白（CREB）、色氨酸代谢、糖皮质激素信号传导和转录降低以及其他几种途径。假设显示先天免疫激活的受试者将显示来自与由相同模型鉴定的机制相关的RDoC域的抑郁症状谱。该亚组应显示接近动机和陈述性（海马）记忆的缺陷，以及唤醒范围内的昼夜节律和睡眠/觉醒结构的异常。

DESCRIPTION (provided by applicant): This proposal for a K23 Mentored Career Development Award describes a program of training and research that will prepare the applicant, Marisa Toups MD, for a career as an independent investigator developing gene expression based biomarkers of immune dysfunction that advance personalized care for depression. The applicant's background in basic immunology research, clinical training, and record of successful productivity particularly suits this proposal to address the need for clinicia scientists working to understand and advance treatment of mood disorders. For successful career development, a comprehensive plan of training and research has been created - the Gene Expression to Expand Knowledge of Inflammatory Depression (GEEK-ID) project - with Dr. Madhukar Trivedi MD and Dr. Robert Danzter DVM, PhD, who serve as the primary mentors for the application. The training component of the GEEK-ID project has two primary aims. Aim 1 is to develop skills needed of an independent investigator performing successful clinical validation of biomarkers for personalized care. This aim builds hands-on skills and training will focus on genome wide gene expression as an experimental method. Training for Aim 1 covers three areas: 1) selection of appropriate study design and statistics for biomarkers trials 2) successful management of clinical operations and data collection, and 3) appropriate collection, processing, storage, and choice of assays for high quality biological data. Aim 2 is to gain knowledge of the functional role of the immune system in mood disorders and how it manifests in immune gene expression. Training will provide the foundational knowledge on which to base skills learned in aim 1. This training involves three areas of understanding: 1) mechanisms of innate immunity 2) mechanisms of communication between the brain and immune system and 3) knowledge of regulation of gene expression in the immune system. The proposed research is designed to identify and characterize a mechanistically distinct subtype of depression featuring innate immune activation. In a cross sectional design, 100 adults with MDD will be clinically phenotyped, and blood RNA sequencing will compare high C Reactive Protein (CRP) and low CRP subjects. It is hypothesized that the CRP associated gene expression pattern will match that of animal and human models of innate immune activation, stress response, and disordered mood. Pathways involved are Mitogen Activated Protein Kinase (MAPK) signaling pathways, transcription factors Nuclear Factor- κß (Nf- κß) and CyclicAMP Response Element Binding Protein (CREB), tryptophan metabolism, decreased glucocorticoid signaling and transcription and several others. It is hypothesized that subjects who show innate immune activation will display a depression symptom profile from RDoC domains related to mechanisms identified by the same models. This subgroup should display deficits in Approach Motivation, and Declarative (Hippocampal) Memory, and abnormalities in Circadian Rhythms and Sleep/Wake constructs within the domain of arousal.