Gene Expression to Expand Knowledge of Inflammatory Depression

描述(由申请人提供)：这份关于K23指导职业发展奖的提案描述了一项培训和研究计划，该计划将为申请者Marisa Toups MD作为一名独立调查员的职业生涯做准备，开发基于基因表达的免疫功能障碍生物标记物，促进对抑郁症的个性化护理。申请人在基础免疫学研究、临床培训和成功的生产力记录方面的背景特别适合这项建议，以满足临床科学家努力了解和推进情绪障碍治疗的需要。为了实现成功的职业发展，已经制定了一个全面的培训和研究计划--扩展炎症性抑郁知识的基因表达(Geek-ID)项目--由Madhukar Trivedi医学博士和Robert Danzter博士博士担任该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。目标1是培养独立研究人员所需的技能，以成功地对个性化护理的生物标记物进行临床验证。这一目标建立了动手技能，培训将重点放在全基因组基因表达作为一种实验方法。目标1的培训包括三个领域：1)为生物标记物试验选择适当的研究设计和统计数据；2)成功地管理临床操作和数据收集；3)适当地收集、处理、存储和选择高质量生物数据的分析方法。目标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。这项培训涉及三个方面的理解：1)先天免疫机制，2)大脑和免疫系统之间的沟通机制，3)免疫系统中基因表达调控的知识。这项拟议的研究旨在识别和描述一种机制上不同的抑郁症亚型，其特征是先天性免疫激活。在一项横断面设计中，100名患有MDD的成年人将进行临床表型分析，血液RNA测序将比较高C反应蛋白(CRP)和低C反应蛋白(CRP)受试者。据推测，CRP相关基因的表达模式将与动物和人类先天免疫激活、应激反应和情绪紊乱的模型相匹配。涉及的信号通路有：丝裂原活化蛋白激酶信号通路、转录因子核因子-κ？和环磷酸腺苷反应元件结合蛋白、色氨酸代谢、糖皮质激素信号和转录减少等。据推测，表现出先天免疫激活的受试者将表现出与相同模型确定的机制相关的RDoC域中的抑郁症状特征。这一亚组应该表现出接近动机和陈述性(海马区)记忆方面的缺陷，以及唤醒领域内昼夜节律和睡眠/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.