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

基本信息

批准号：
8323833
负责人：
Qisheng Zhang
金额：
$ 27.81万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
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/8323833
关键词：
ADP-Ribosylation Factor 1 ADP-Ribosylation Factors ARFGAP1 Address Affect Affinity Chromatography Alzheimer&apos 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

项目摘要

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 GTP 酶激活蛋白 (ARFGAP) 形成一个蛋白家族，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，ARFGAP 调节不同疾病的详细机制尚不清楚。长期目标是更好地了解 ARFGAP 直接调节的蛋白质网络，并开发不同 ARFGAP 的小分子调节剂来剖析其生物学功能。这一特殊应用建立在之前发现的 QS11 的基础上，QS11 是一种小分子，可与 Wnt 蛋白协同作用，通过抑制多个 ARFGAP 来激活 Wnt/2-catenin 信号通路。目标是使用和完善 QS11 来剖析 ARFGAP 调节的细胞信号传导。具体来说，我们将追求三个目标：1）明确QS11抑制ARFGAP的分子基础； 2) 鉴定对 ARFGAP 具有更高效力和选择性的 QS11 类似物； 3) 明确抑制 ARFGAP 导致 Wnt 协同作用的机制。在第一个目标下，将应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，文库合成和合理设计将用于提高 QS11 对 ARFGAP 的效力和选择性。第三个目标将使用生化和遗传工具来了解 QS11 对 ARFGAP 的抑制如何导致其 Wnt 协同作用。拟议的研究意义重大，因为它将产生第一组小分子调节剂，这些调节剂可以在细胞培养物和整个生物体中在时间和空间上扰乱 ARFGAP 相关的细胞信号传导。这种扰动对于理解 ARFGAP 在疾病中的作用至关重要。此外，拟议的研究将在 ARFGAP 和 Wnt/2-catenin 信号通路之间建立新的联系。