Developing Small Molecule ARFGAP Regulators to Dissect Cell Signaling

开发小分子 ARFGAP 调节剂来剖析细胞信号传导

• 批准号: 8540437
• 负责人: Qisheng Zhang
• 金额: $ 26.83万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8540437
• 关键词: ADP-Ribosylation Factor 1; ADP-Ribosylation Factors; ARFGAP1; Address; Affect; Affinity Chromatography; Alzheimer' s Disease; Area; Autistic Disorder; Binding; Biochemical Genetics; Biological Assay; Biological Process; Biology; Cell Culture Techniques; Cell-Cell Adhesion; Cells; Chemicals; Complementary DNA; Complex; Cytoskeleton; Data; Disease; Dose; Endocytosis; Family member; GTP Binding; GTPase-Activating Proteins; Genetic; Genetic Transcription; Goals; Guanine Nucleotide Exchange Factors; Guanosine Triphosphate; Human Development; Human Genome; Hydrolysis; Individual; Inhibitory Concentration 50; Lead; Libraries; Ligands; Link; Malignant Neoplasms; Mammals; Mediating; Molecular; Monomeric GTP-Binding Proteins; Neurodegenerative Disorders; Phenotype; Play; Positioning Attribute; Protein Family; Proteins; Protocols documentation; Public Health; RNA Interference; Regulation; Reporting; Research; Resolution; Role; S Phase; Signal Pathway; Signal Transduction; Signaling Protein; Site; Solid; Specificity; Structure; Techniques; Testing; Therapeutic; Time; Vesicle; Whole Organism; Wnt proteins; Wnt-3A protein; Work; Zinc; analog; base; biological systems; cell motility; clinically significant; design; drug discovery; improved; inhibitor/antagonist; insight; migration; mutant; neuron development; novel; novel strategies; purine analog; receptor; research study; small molecule; tool; trafficking; tumor progression; xenopus development

DESCRIPTION (provided by applicant): GTPase-activating proteins of ADP-ribosylation factors (ARFGAPs) form a family of proteins that play key roles in cell adhesion and migration, tumor progression, as well as neuronal development. A body of evidence also indicates that ARFGAPs are involved in various diseases, including cancer, Alzheimer's disease, and autism. However, the detailed mechanism by which ARFGAPs regulate different diseases is largely unknown. The long-term goals are to better understand the network of proteins directly modulated by ARFGAPs, and to develop small molecule regulators of distinct ARFGAPs to dissect their biological functions. This particular application is built on the previous discovery of QS11, a small molecule that synergizes with Wnt proteins to activate the Wnt/2-catenin signaling pathway through inhibition of multiple ARFGAPs. The objective is to use and refine QS11 to dissect ARFGAP-regulated cell signaling. Specifically, we will pursue three aims: 1) Define the molecular basis for the inhibition of ARFGAPs by QS11; 2) Identify QS11 analogs with higher potency and selectivity against ARFGAPs; and 3) Define the mechanism by which the inhibition of ARFGAP leads to Wnt synergy. Under the first aim, two complementary approaches will be applied to clarify the mechanistic details of ARFGAP inhibition by QS11. Under the second aim, both library synthesis and rational design will be used to improve QS11's potency and selectivity against ARFGAPs. Under the third aim, biochemical and genetic tools will be used to understand how inhibition of ARFGAPs by QS11 leads to its Wnt synergy. The proposed research is significant, because it will lead to the first sets of small molecule regulators that can temporally and spatially perturb ARFGAP-associated cell signaling, both in cell culture and in whole organisms. Such perturbation is essential to understand the roles for ARFGAPs in diseases. In addition, the proposed research will establish a novel link between ARFGAPs and the Wnt/2-catenin signaling pathway.

描述（由申请人提供）：adp核糖基化因子的gtpase激活蛋白（ARFGAPs）形成了一个蛋白家族，在细胞粘附和迁移、肿瘤进展以及神经元发育中发挥关键作用。大量证据还表明，arfgap与多种疾病有关，包括癌症、阿尔茨海默病和自闭症。然而，ARFGAPs调控不同疾病的详细机制在很大程度上是未知的。长期目标是更好地了解由arfgap直接调节的蛋白质网络，并开发不同arfgap的小分子调节剂，以解剖其生物学功能。这种特殊的应用是建立在先前发现的QS11之上的，QS11是一种与Wnt蛋白协同作用的小分子，通过抑制多种ARFGAPs来激活Wnt/2-catenin信号通路。目的是利用和完善QS11来剖析arfgap调控的细胞信号。具体而言，我们将追求三个目标：1)确定QS11抑制arfgap的分子基础；2)鉴定出对arfgap具有较高效价和选择性的QS11类似物；3)明确ARFGAP抑制导致Wnt协同作用的机制。在第一个目标下，我们将采用两种互补的方法来阐明QS11抑制ARFGAP的机制细节。在第二个目标下，将通过文库合成和合理设计来提高QS11对arfgap的效力和选择性。在第三个目标下，将使用生化和遗传工具来了解QS11如何抑制ARFGAPs导致其Wnt协同作用。这项提议的研究意义重大，因为它将导致第一批小分子调节剂，这些调节剂可以在时间和空间上干扰细胞培养和整个生物体中与arfgap相关的细胞信号。这种扰动对于理解arfgap在疾病中的作用至关重要。此外，本研究将在ARFGAPs和Wnt/2-catenin信号通路之间建立新的联系。