Grant: Foundation Grant

Biomarkers; Cancer; Conditional Knockout Mice; Hiv; Influenza; Lymphocytic Choriomeningitis Virus; Multiparameter Flow Cytometry; Rheumatoid Arthritis; Single Nucleotide Polymorphisms; Tnfr Superfamily

<html> <body> <p>The immune system must strike a fine balance to control infection while avoiding lethal pathology. TNFR family members (TNFRs) play key roles in maintaining this balance. The broad goal of my research program is to understand how TNFRs regulate the magnitude and duration of T cell responses to infection and to extend this work to understand how the dysregulation of these pathways impacts human disease. This research will provide new insights that will inform vaccine and immunotherapeutic strategies and potentially identify new biomarkers to evaluate vaccine efficacy or predict disease or therapeutic outcome.<br> <br> The proposed program integrates 3 currently active CIHR grants, Costimulation of Human T cell activation, TNFRs in control of chronic infection, and TNFRs in control of respiratory infection. The program will cover 3 interrelated thematic areas: <b>1. How do TNFRs regulate immunity to acute and chronic viral infections?</b> The TNFRs 4-1BB and GITR have differential roles in viral infection, depending on context (mild vs. severe influenza, acute vs. chronic LCMV). By identifying the cellular and tissue-specific interactions that govern these differential effects, we will gain new insights to appropriately target vaccine or immunotherapeutic strategies. <b>2<i>.</i></b> <b>How do TRAF proteins contribute to control of infection</b><b>?</b> TNFRs signal by recruiting TRAF signaling adaptors (TRAFs 1-6). Little is known about how differential recruitment of TRAF family members signals different outcomes. We will compare membrane proximal and distal (transcriptional) events downstream of a TRAF1/2-binding TNFR (4-1BB) and a TRAF2/5-binding TNFR (GITR) to gain new insights into the consequences of differential TRAF recruitment. <b>3.</b> <b>How does TRAF1 impact human disease?</b> TRAF1 is emerging as a key regulator of human disease. TRAF1 is lost from chronically stimulated HIV-specific CD8 T cells with progression of infection, but overexpressed in B cell related cancers. Moreover, single nucleotide polymorphisms (SNPs) in TRAF1 are linked to severity of rheumatic disease. With clinical collaborators, we will explore the role of TRAF1 in these disease settings and investigate TRAF1 as a potential biomarker for predicting disease outcome or therapeutic efficacy.<br> <br> The proposed program is underpinned by strong expertise in my team in cellular immunology, mouse infection models, multi-parameter flow cytometry and molecular signaling studies in primary mouse and human cells. We benefit from a rich environment with outstanding collaborators, well-defined clinical cohorts, and core facilities that provide training /services in flow cytometry, CyToF, sophisticated microscopy, pathology and genomics/proteomics platforms.<br> <br> I am deeply committed to training students and fellows. My program provides substantial training opportunities, from basic mouse immunology to human T cell biology and translational work in biomarker development. Trainees will benefit from exposure to diverse approaches in an outstanding environment. Our collaborations with the GSK drug discovery program and clinical collaborators expose trainees to translational research. Our department graduate/post-doctoral programs are enriched by a vibrant departmental seminar program, outreach and career development activities.<br> <br> <i>Our program will provide exceptional training and knowledge in immune regulation by TNFRs and the translation of this knowledge to develop new biomarkers and inform immunotherapeutic strategies.</i> </p> </body> </html>