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
基本信息
- 批准号:10656002
- 负责人:
- 金额:$ 66.27万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:Animal ModelBindingBiological AssayBiologyCell Migration Inhibition functionCell modelCell physiologyCellsChemicalsChemotaxisChronicDataDesmoplasticDevelopmentDiseaseDisease ProgressionDuctal Epithelial CellElementsEpithelial CellsFibrosisFunctional disorderG-Protein-Coupled ReceptorsGPR2 geneGoalsHealthHot SpotImmuneImmune responseImmunotherapyInfiltrationInflammationInflammatory ResponseKineticsKnockout MiceKnowledgeLigandsLinkMalignant - descriptorMalignant NeoplasmsMapsMeasuresMethodsModelingMolecularMucositisMucous MembraneNeoplasmsOrganPancreasPancreatic Ductal AdenocarcinomaPancreatic ductPancreatitisPatientsPharmacologyPhysiologicalPlayProtein SecretionPublic HealthPublishingRegulatory T-LymphocyteResearchRisk FactorsRoleSignal TransductionSiteStructural ModelsStructureT cell infiltrationTestingTherapeuticTissuesTumor PromotionWorkcell motilitychemokinechemokine receptorchronic pancreatitisdesigndrug discoveryeffector T cellhigh throughput screeningimprovedin vitro Modelin vivoinhibitormolecular modelingmouse modeloverexpressionpancreas developmentpharmacologicpremalignantprogramsreceptorrecruitresponsescreeningsmall moleculesmall molecule inhibitortherapeutic targettraffickingtumortumor growthtyrosine O-sulfate
项目摘要
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.
修改项目摘要/摘要部分
该项目的目标是确定CCL 28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这种分泌蛋白的小分子抑制剂。CCL 28是一种粘膜趋化因子,通过募集表达G蛋白偶联受体CCR 10的调节性T细胞(TCL 28)来促进多种器官中的肿瘤生长。基于我们已发表的初步结果,我们假设胰腺导管上皮细胞分泌趋化因子CCL 28也会导致慢性炎症进展为恶性疾病。我们假设,抑制CCL 28活性将改变胰腺粘膜微环境,从而减少癌前炎症并增强现有化疗和免疫治疗的活性。为了实现这一目标,我们提出了三个概念上相互联系,但实验独立的具体目标。首先,我们将在慢性胰腺炎的动物模型中测试我们的机制假设,以实验证明通过CCR 10的CCL 28活性在体内纤维炎症反应中起关键作用,并开发可用于筛选有希望的抑制剂的体外模型(目的1)。将使用NMR和分子建模详细绘制CCL 28通过其G蛋白偶联受体CCR 10识别的关键要素,并且我们将使用最先进的受体药理学分析平台来定义该趋化因子受体的完整细胞内信号传导谱(目的2)。使用CCL 28的解析NMR结构和其磺基酪氨酸结合口袋的知识,我们将采用在Bristman实验室开发的基于结构的策略,该策略能够发现结合特定趋化因子靶点并抑制细胞迁移的小分子(目的3)。总的来说,所提出的研究将为我们理解以下方面提供根本性进展:(1)胰腺中的Treg功能和病理生理学,(2)在很大程度上未经检查的趋化因子信号传导轴中配体-受体选择性和GPCR药理学的结构基础,以及(3)粘膜趋化因子在慢性炎症和肿瘤形成的肿瘤促进界面处的可药用性。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Michael B Dwinell其他文献
Michael B Dwinell的其他文献
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{{ truncateString('Michael B Dwinell', 18)}}的其他基金
Biased chemokine receptor signaling in cancer progression
癌症进展中偏向的趋化因子受体信号传导
- 批准号:
10077789 - 财政年份:2019
- 资助金额:
$ 66.27万 - 项目类别:
Biased chemokine receptor signaling in cancer progression
癌症进展中偏向的趋化因子受体信号传导
- 批准号:
10541844 - 财政年份:2019
- 资助金额:
$ 66.27万 - 项目类别:
Biased chemokine receptor signaling in cancer progression
癌症进展中偏向的趋化因子受体信号传导
- 批准号:
10321201 - 财政年份:2019
- 资助金额:
$ 66.27万 - 项目类别:
Targeting pancreatic cancer energy metabolism, tumor growth, and metastasis
针对胰腺癌能量代谢、肿瘤生长和转移
- 批准号:
8696182 - 财政年份:2014
- 资助金额:
$ 66.27万 - 项目类别:
Targeting pancreatic cancer energy metabolism, tumor growth, and metastasis
针对胰腺癌能量代谢、肿瘤生长和转移
- 批准号:
9281690 - 财政年份:2014
- 资助金额:
$ 66.27万 - 项目类别:
Targeting pancreatic cancer energy metabolism, tumor growth, and metastasis
针对胰腺癌能量代谢、肿瘤生长和转移
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8883430 - 财政年份:2014
- 资助金额:
$ 66.27万 - 项目类别:
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