Grant: Doctoral Award - Frederick Banting and Charles Best Canada Graduate Scholarships

Glucocorticoids (GCs) are steroid hormones released from the adrenal glands during stress, and GCs have important effects on the immune system. GCs reduce inflammation and increase programmed cell death of immature lymphocytes during development. High GC levels during early human development, when the immune system is not yet mature, have long-lasting negative effects on adult immune function. GCs in systemic circulation are low and unresponsive to stress during this time. However, GC levels in early development are actually high in immune organs. The presence of high GC concentrations in lymphoid organs raises the hypothesis that these organs synthesize their own GCs to maintain high local levels. If so, GC concentrations in lymphoid tissues must also be regulated, raising a second hypothesis that corticotropin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) regulate immune GC production, as they do with adrenal GC production. The presence of high local GC concentrations in early life leads to a third hypothesis, that GCs are important in lymphocyte development and immune maturation. Using animal models, I will determine whether GCs are locally synthesized in lymphoid tissues, whether they are regulated locally by CRH and ACTH, and whether they are important in lymphocyte development. I will test for GC production by incubating lymphoid tissue with a labeled precursor and identifying downstream metabolites. To determine if CRH and ACTH regulate lymphoid GC production, I will first measure CRH and ACTH in immune tissues, and then measure GC production after CRH and ACTH treatment. To determine the importance of GCs in lymphocyte development, I will compare development of lymphocyte populations in the presence and absence of GC signals. Together, these studies will determine how GCs are produced and regulated in primary lymphoid tissue, and whether they play a critical role in lymphocyte maturation.