Multivalent Ligands as Effectors

作为效应器的多价配体

• 批准号: 6519823
• 负责人: Laura L Kiessling
• 金额: $ 29.1万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-06-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6519823
• 关键词: Bacillus subtilis; Escherichia coli; G protein; Proteus; biological signal transduction; cell differentiation; chemoattractants; chemokine; chemoreceptors; chemotaxis; ligands; method development; peptide library; protein structure function; receptor binding

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.

拟议研究的总体目标是了解细胞如何控制其对环境中刺激的反应，并开发可以调节这些反应的配体。 配体与细胞表面受体的结合会产生信号。它的幅度和持续时间可能会受到受体职业变化的影响。 我们假设通过受体聚类也实现了信号扩增和整合。 合成多价配体非常适合研究受体聚类对信号输出的贡献。 由于多价配体可以影响细胞表面受体占用和聚类，因此我们建议检查它们作为效应子的效用（引起细胞反应的化合物）。 在系统中，我们将研究细菌和白细胞趋化性，我们假设信号扩增和整合是通过扩展的受体阵列发生的。 通过在这些阵列中与受体的非共价相互作用的形成，多价配体可以稳定可以传递信息的超分子复合物。 为了检验这一假设，我们将探讨多价配体的结构与促进细菌或白细胞趋化性的能力之间的关系。该提案的具体目的是：1）开发方法来合成在识别元件身份，长度和形状中变化的多价配体的库； 2）探索对合成多价配体的细菌趋化反应，并探测引起这些反应的机制； 3）检查合成多价配体影响蜂群细胞分化的能力； 4）研究中性粒细胞对通过N-甲基肽受体介导的合成多合体的趋化反应，这是趋化因子/趋化因子/趋化因子G蛋白偶联受体（GPCR）家族的成员。 对控制细菌趋化性的机制的理解对于制定操纵原核信号事件的方法很重要。作为改变细菌趋化性的配体的应用，我们将研究它们干扰致病性蜂群分化的能力。 我们对白细胞趋化性的研究可能会导致控制炎症的新策略，并更深入地了解受体聚类在GPCR介导的信号扩增和整合中的作用。