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- ? (Nf- ?) 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.
This application describes a training and research plan for professional development addressing the need for clinician scientists developing mechanism-targeted treatment strategies for patients with mood disorders. The goals of the research are to better understand patients with both depression and abnormal immune system function and learn if specific immune pathways are associated with particular symptoms of depression.