Function of the Sts protein phosphodiesterase domain

Sts蛋白磷酸二酯酶结构域的功能

基本信息

批准号：
10407644
负责人：
Jarrod B French
金额：
$ 19.57万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-19 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10407644
关键词：
Address Animal Model Animals Biochemical Biological Biological Assay C-terminal Candida albicans Cell model Cells Chemistry Communicable Diseases Data Development Enzymes Foundations Francisella tularensis Generations Genetic Goals Histidine Human Activities Hydrophobicity Immune Immune response Immune signaling Immune system Immunologics Infection Inflammation Kinetics Knowledge Lead Mammalian Cell Modeling Molecular Mus N-terminal Nature Nucleic Acids Nucleotides Outcome Periodicity Phosphoric Monoester Hydrolases Play Property Proteins Public Health Research Resistance Role SH3 Domains Signal Pathway Signal Transduction Specificity Staphylococcus aureus Structure Substrate Domain Substrate Specificity Surface Testing Therapeutic Ubiquitin Virulent Work antimicrobial base clinically relevant enzyme activity immunoregulation infectious disease treatment innovation insight member metabolomics mouse model novel novel therapeutics pathogen pathogenic bacteria pathogenic fungus pathogenic microbe phosphoric diester hydrolase receptor response targeted treatment translational impact

项目摘要

PROJECT SUMMARY The Sts proteins (Sts-1 and -2) negatively regulate signaling pathways within cells of the mammalian immune system. Mice lacking Sts expression (Sts-/-) are profoundly resistant to infection by clinically relevant fungal and bacterial pathogens, including Candida albicans, Francisella tularensis, and Staphylococcus aureus. Resistance is associated with rapid pathogen clearance and reduced inflammation. We recently identified a novel, functionally relevant, phosphodiesterase (PDE) enzyme activity of Sts-1. We hypothesize that this unprecedented activity plays a key role in regulating immune cell signaling pathways. To fulfill our long-term goal of developing novel therapies for infectious diseases, the objective of this proposal is to elucidate the signaling role of the Sts-1 PDE domain and identify molecular determinants of its function. Guided by strong preliminary data, we will test our hypothesis and accomplish our overall objective by pursuing the following two specific aims: 1) Elucidate the role of the Sts PDE domain in negatively regulating immune cell signaling pathways; and 2) Identify the substrate, and define the molecular determinants of function of the Sts PDE domain. In the first aim, we will utilize cell- and animal-based models to evaluate Sts-1 PDE domain function. In the second aim, we will use both a targeted, kinetics-based approach and global metabolomics to define Sts-1 PDE domain substrate breadth and specificity. In addition, we will determine the mechanism and molecular features that define the enzyme’s function. The proposed studies are innovative because they focus on a newly discovered enzyme domain that has previously not been characterized. The proposed research is significant because it is expected to substantially expand our understanding of the role of the Sts proteins in regulating immune cell responses. As therapeutic down-modulation of Sts function is expected to increase resistance to select microbial pathogens, we aim to exploit the results of these studies to develop new anti-microbial therapies that target the Sts-1 PDE domain.

项目摘要 STS蛋白（STS -1和-2）负调节哺乳动物免疫细胞内的信号通路系统。缺乏STS表达的小鼠（STS - / - ）对通过临床相关的真菌和细菌病原体，包括白色念珠菌，francisella tularensis和金黄色葡萄球菌。反抗与快速病原体清除和炎症减少有关。我们最近确定了一部小说 STS-1的功能相关，磷酸二酯酶（PDE）酶活性。我们假设这是前所未有的活性在调节免疫细胞信号通路方面起关键作用。实现我们的长期目标为了开发用于传染病的新型疗法，该提案的目的是阐明信号 STS-1 PDE结构域的作用并确定其功能的分子决定剂。在强大的初步指导下数据，我们将通过追求以下两个具体目标来检验我们的假设并实现我们的整体目标： 1）阐明STS PDE结构域在负调控的免疫电池信号通路中的作用；和 2）识别底物，并定义STS PDE结构域功能的分子决定剂。在第一个目标中，我们将利用基于细胞和动物的模型来评估STS-1 PDE域功能。在第二个目的，我们将使用针对性的基于动力学的方法和全球代谢组学来定义STS-1 PDE 域基材的宽度和特异性。此外，我们将确定机制和分子特征这定义了酶的功能。拟议的研究具有创新性，因为它们专注于新的发现以前未表征的酶结构域。拟议的研究很重要因为预计它将大大扩展我们对STS蛋白在调节中的作用的理解免疫细胞反应。由于预期STS功能的治疗性下调将增加对选择微生物病原体，我们旨在探索这些研究的结果以开发新的抗微生物疗法该靶向STS-1 PDE域。