Grant: Discovery Grants Program - Individual

Inflammation is a natural physiological process essential for the maintenance of tissue homeostasis. Spearheaded by sentinel cells of the immune system, sophisticated intra- and intercellular signaling mechanisms direct context-dependent responses in the face of diverse and continual environmental challenge. Immunity is shaped by cell-type-specific receptor-mediated signals that collectively determine the nature of each response. These critical communication channels shape inflammation in time, space, and immune phenotype. Given the role of inflammation in modulating organismal structure and function, understanding the fundamental responses that shape this process is paramount. Mast cells are tissue resident immune sentinels that are responsive to a diverse array of environmental challenges and play a central role in shaping local inflammation based on context-dependent molecular signaling events. Upon arrival as immature progenitor cells, the local tissue microenvironment shapes heterogeneous mast cell phenotypes according to the molecular (e.g., cytokines, growth factors) and cellular/tissue (e.g., connective, mucosal) milieu in which they remain as long-lived first-responders. Beyond their complex phenotypic range, their position of enrichment at environmental interfaces necessitates that mast cells detect and respond to diverse extracellular cues, ranging from allergens and pathogens through to cytokines, growth factors, and stress. Our Inflammation & Immunity Lab's long-term research program has a unique lens on the form and function of mast cell activity and mechanisms that program their fundamental immunomodulatory role in inflammation. We hypothesize that mast cell inflammatory programing is shaped by these critical signaling functions in differentiation as well as receptor-mediated and calcium-dependent signaling integration and synergy. To examine these foci of mast cell programming, we will investigate the following short-term objectives: 1. Programming of mast cell activity during differentiation via JNK. 2. Hubs of signal-integration in mast cell activation: the novel role of TAK1. 3. Calcium-mediated signaling during mast cell activation: the novel role of neurogranin Impact: Inflammation is a central and fundamental physiological process that enables tissue homeostasis and the coordinated response to insult from injury, stress, and environmental challenge. Mast cells are a focal point and key regulator coordinating the dynamic nature, duration and extent of the normal inflammatory response in these diverse contexts. Understanding the levers that influence the extent of mast cell-directed inflammation has broad applicability, and offers a long-lived cellular depot embedded in tissues that may be targeted to manage the positive and negative aspects of inflammation in day-to-day normal activities (exercise, wound healing) through to pathological acute and chronic contexts (allergy, asthma, infection).