Function of the Sts protein phosphodiesterase domain

Sts蛋白磷酸二酯酶结构域的功能

• 批准号: 10301950
• 负责人: Jarrod B French
• 金额: $ 24.96万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-19 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10301950
• 关键词: Address; Animal Model; Animals; Biochemical; Biological; Biological Assay; C-terminal; Candida albicans; Cell model; Cells; Chemistry; Cleaved cell; 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

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Sts-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-/-）对临床相关真菌感染具有深刻的抗性， 细菌病原体，包括白色念珠菌、土拉弗朗西斯菌和金黄色葡萄球菌。电阻 与快速清除病原体和减少炎症有关。我们最近发现了一本小说， Sts-1的功能相关的磷酸二酯酶（PDE）活性。我们假设这 前所未有的活性在调节免疫细胞信号传导途径中起着关键作用。为了实现我们的长期目标 为了开发感染性疾病的新疗法，本提案的目的是阐明 Sts-1 PDE结构域的作用，并确定其功能的分子决定因素。以强有力的初步指导 数据，我们将通过追求以下两个具体目标来测试我们的假设并实现我们的总体目标： 1)阐明Sts PDE结构域在负调节免疫细胞信号传导途径中的作用;和 2)确定底物，并定义Sts PDE结构域功能的分子决定因素。 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结构域功能。在 第二个目标，我们将使用靶向的、基于动力学的方法和整体代谢组学来定义Sts-1 PDE 域底物宽度和特异性。此外，我们将确定其机制和分子特征 定义酶的功能。拟议的研究是创新的，因为他们专注于一个新的 发现了以前没有被表征的酶结构域。所提出的研究是有意义的 因为它有望大大扩展我们对Sts蛋白在调节 免疫细胞反应。由于Sts功能的治疗性下调预期会增加对 选择微生物病原体，我们的目标是利用这些研究的结果来开发新的抗微生物疗法 靶向Sts-1 PDE结构域。