Structure-based inhibition of chemokine signaling in the inflamed pancreas

基于结构的炎症胰腺趋化因子信号传导抑制

• 批准号: 10656002
• 负责人: Michael B Dwinell
• 金额: $ 66.27万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-20 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656002
• 关键词: Animal Model; Binding; Biological Assay; Biology; Cell Migration Inhibition function; Cell model; Cell physiology; Cells; Chemicals; Chemotaxis; Chronic; Data; Desmoplastic; Development; Disease; Disease Progression; Ductal Epithelial Cell; Elements; Epithelial Cells; Fibrosis; Functional disorder; G-Protein-Coupled Receptors; GPR2 gene; Goals; Health; Hot Spot; Immune; Immune response; Immunotherapy; Infiltration; Inflammation; Inflammatory Response; Kinetics; Knockout Mice; Knowledge; Ligands; Link; Malignant - descriptor; Malignant Neoplasms; Maps; Measures; Methods; Modeling; Molecular; Mucositis; Mucous Membrane; Neoplasms; Organ; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic duct; Pancreatitis; Patients; Pharmacology; Physiological; Play; Protein Secretion; Public Health; Publishing; Regulatory T-Lymphocyte; Research; Risk Factors; Role; Signal Transduction; Site; Structural Models; Structure; T cell infiltration; Testing; Therapeutic; Tissues; Tumor Promotion; Work; cell motility; chemokine; chemokine receptor; chronic pancreatitis; design; drug discovery; effector T cell; high throughput screening; improved; in vitro Model; in vivo; inhibitor; molecular modeling; mouse model; overexpression; pancreas development; pharmacologic; premalignant; programs; receptor; recruit; response; screening; small molecule; small molecule inhibitor; therapeutic target; trafficking; tumor; tumor growth; tyrosine O-sulfate

Modified Project Summary/Abstract Section The goal of this project is to establish the role of CCL28 in chronic pancreatitis and use structure-based drug discovery methods to identify small molecule inhibitors of this secreted protein. CCL28 is a mucosal chemokine that promotes tumor growth in a variety of organs by recruiting regulatory T cells (Tregs) that express the G protein-coupled receptor CCR10. Based on our published and preliminary results, we postulate that secretion of the chemokine CCL28 by pancreatic ductal epithelial cells also drives chronic inflammation that progresses to malignant disease. We hypothesize that inhibition of CCL28 activity will alter the pancreatic mucosal microenvironment in a manner that reduces pre-malignant inflammation and enhances the activity of existing chemotherapeutics and immunotherapies. To achieve this objective, we propose three conceptually linked but experimentally independent specific aims. First, we will test our mechanistic hypothesis in animal models of chronic pancreatitis, to demonstrate experimentally that CCL28 activity through CCR10 plays a key role in the fibroinflammatory response in vivo and develop an in vitro model that can be used to screen promising inhibitors (aim 1). Key elements of CCL28 recognition by its G protein-coupled receptor CCR10 will be mapped in detail using NMR and molecular modeling, and we will define the complete intracellular signaling profile of this chemokine receptor using state-of-the-art assay platforms for receptor pharmacology (aim 2). Using the solved NMR structure of CCL28 and knowledge of its sulfotyrosine binding pocket, we will employ a structure-based strategy developed in the Volkman lab that enables the discovery of small molecules that bind a specific chemokine target and inhibit cell migration (aim 3). Collectively, the proposed studies will provide fundamental advances in our understanding of (1) Treg function and pathophysiology in the pancreas, (2) the structural basis for ligand-receptor selectivity and GPCR pharmacology in a largely unexamined chemokine signaling axis, and (3) the druggability of a mucosal chemokine at the tumor-promoting interface of chronic inflammation and neoplasia.

修改的项目摘要/摘要部分 该项目的目的是确定CCL28在慢性胰腺炎中的作用，并使用基于结构的药物发现方法来鉴定该分泌蛋白的小分子抑制剂。 CCL28是一种粘膜趋化因子，通过募集表达G蛋白偶联受体CCR10的调节性T细胞（TREG）来促进各种器官的肿瘤生长。基于我们发表的初步结果，我们假设胰腺导管上皮细胞对趋化因子CCL28的分泌也引发了慢性炎症，从而发展为恶性疾病。我们假设抑制CCL28活性会以减少机构前炎症并增强现有化学疗法和免疫疗法的活性的方式改变胰腺粘膜微环境。为了实现这一目标，我们提出了三个在概念上连接但在实验上独立的特定目的。首先，我们将在慢性胰腺炎动物模型中检验我们的机械假设，以实验证明，通过CCR10的CCL28活性在体内的肌炎反应中起关键作用，并开发可用于筛选有希望的抑制剂的体外模型（AIM 1）。 CCL28通过其G蛋白偶联受体CCR10识别的关键要素将使用NMR和分子建模详细绘制，我们将使用最新的受体药理学（AIM 2）使用最新的趋化因子测定平台来定义该趋化因子受体的完整细胞内信号传导谱。使用CCL28的NMR结构及其磺胺酪氨酸结合口袋的知识，我们将采用在Volkman Lab中开发的基于结构的策略，从而可以发现结合特定趋化因子靶标并抑制细胞迁移的小分子（AIM 3）。拟议的研究总的来说，在胰腺中（1）TREG功能和病理生理学的理解中，（2）在很大程度上未经研究的趋化因子信号传导中，（3）粘液式化合物的药物与粘液型相互作用的粘液式相互作用，在很大程度上未经证实的趋化因子信号传导中，在很大程度上未经研究的趋化因子信号传导中，在很大程度上未经研究的趋化因子信号传导和GPCR药理学方面的结构基础。