Multivalent Ligands as Effectors

University Of Wisconsin Madison, Madison WI

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Abstract

The overall objectives of the proposed research are to understand how cells control their responses to stimuli in the environment and to develop ligands that can regulate these responses. The binding of a ligand to a cell surface receptor can give rise to a signal; its magnitude and duration can be influenced by changes in receptor occupation. We hypothesize that signal amplification and integration is also achieved through receptor clustering. Synthetic multivalent ligands are ideally suited to investigating the contributions of receptor clustering to signal output. Because multivalent ligands can influence cell surface receptor occupation and clustering, we propose to examine their utility as effectors (compounds that elicit a cellular response). In the systems we shall investigate, bacterial and leukocyte chemotaxis, we hypothesize that signal amplification and integration occurs via extended receptor arrays. Through the formation of non-covalent interactions with receptors in these arrays, multivalent ligands can stabilize supramolecular complexes through which information can be transferred. To test this hypothesis, we will explore the relationship between the structure of a multivalent ligand and its ability to promote chemotaxis of bacteria or leukocytes. The specific aims of this proposal are: 1) to develop methods to synthesize libraries of multivalent ligands that vary in recognition element identity, length, and shape; 2) to explore bacterial chemotactic responses to synthetic multivalent ligands and to probe the mechanisms by which these responses are elicited; 3) to examine the ability of synthetic multivalent ligands to influence swarmer cell differentiation; and 4) to investigate the chemotactic responses of neutrophils to synthetic multivalent ligands mediated through the N-formyl peptide receptor, a member of the chemoattractant/chemokine G protein- coupled receptor (GPCR) family. An understanding of the mechanisms that control bacterial chemotaxis is important for devising approaches to manipulate prokaryotic signaling events. As an application of our ligands that alter bacterial chemotaxis, we will investigate their ability to interfere with differentiation of pathogenic swarmer cells. Our studies of leukocyte chemotaxis may lead to new strategies for the control of inflammation and a deeper understanding of the role of receptor clustering in GPCR-mediated signal amplification and integration.