Neutrophils constitute the largest class of white blood cells and are at front line of cellular immune defense. They are able to sense and migrate up concentration gradients of chemoattractants in search of primary sites of inflammation in a process termed chemotaxis. These chemoattractants include formylated peptides, complement, and various chemokines. Each chemoattractant binds to a specific receptor that activates a number of responses including chemotaxis. While much is known about the molecular interactions and signaling pathways that regulate the response to individual cues, little is known about how these pathways process multiple cues to effect migration in the appropriate direction. Furthermore, neutrophils do not simply respond to these cues but also directly regulate their production. The overall goal of the proposed research is to understand how neutrophils integrate multiple chemotactic cues in order to target sites of inflammation and clear infections.
The specific aims of the proposal are: (1) quantify how neutrophils migrate in response to different combinations of chemoattractant gradients;(2) determine the intracellular mechanisms to regulate chemotaxis in response to multiple cues;and (3) elucidate the roles of different chemotactic cues in coordinating neutrophils during the immune response. Central to overall goal and specific aims of the proposal is the development of a multiscale model of neutrophil chemotaxis that will directly link intracellular mechanisms with macroscale cellular behaviors. To facilitate model develop and simulation, we propose a novel computational framework for multiscale integration. To test and refine this model, a number of experiments targeting different scales of resolution are proposed. In order to perform experiments involving multiple chemoattractant gradients, we propose a novel microscale platform for generating gradients and assaying chemotaxis. If successful, the proposed research will uncover the intracellular regulatory mechanisms used by neutrophils to integrate and prioritize multiple chemotactic cues. The resulting model will help us understand how aberrant signaling and defects in neutrophil chemotaxis lead to diseases such as asthma and rheumatoid arthritis and guide the development of improved therapeutic for treating these diseases.
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