Salicylic Acid in Immunity and Health: A Small Phytohormone with Big Physiological Impacts

水杨酸在免疫和健康中的作用：一种具有巨大生理影响的小植物激素

• 批准号: 10358488
• 负责人: Xinnian Dong
• 金额: $ 39.75万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10358488
• 关键词: Address; Agriculture; Animals; Apoptosis; Aspirin; Biological Response Modifiers; Biology; Cardiovascular Diseases; Cell Death; Cell Nucleus; Cell Survival; Cell physiology; Cells; Chemicals; Clinical Trials; Colon Carcinoma; Complex; Conflict (Psychology); Cytoplasm; Desiccation; Development; Distal; Engineering; Ensure; Environmental Hazards; Fever; Funding; Genes; Growth; Health; Health Hazards; Hemorrhage; Herbal Medicine; Immune response; Immune signaling; Immune system; Immunity; Infection; Light; Mediating; Medicine; Mission; Modeling; Molecular; National Institute of General Medical Sciences; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Nuclear Pore Complex; Nuclear Translocation; Organism; Periodicity; Permeability; Pesticides; Physiological; Plant Growth Regulators; Plants; Play; Process; Production; Regulation; Research; Resistance; Role; Salicylic Acids; Site; Testing; Time; Tissues; cancer type; circadian pacemaker; combat; drug efficacy; genetic analysis; immunoregulation; mutant; pain relief; pathogen; side effect; transcriptome; ubiquitin ligase

The essence of an immune system is to ensure defense against pathogens without collateral damage to self. In plants, this is accomplished, in part, through the regulation of the immune signal salicylic acid (SA). Production of SA during the effector-triggered immunity (ETI) is associated with programmed cell death (PCD) of the infected cells to restrict pathogen growth at the site of infection and survival of distal cells with broad-spectrum systemic acquired resistance (SAR). This binary function of SA is achieved through activities of NPR1. NPR1 is not only a master immune regulator, but also involved in key cellular functions, such as the circadian clock. In the absence of pathogen challenge, SA is rhythmically produced through the direct regulation of the clock component CHE and subsequently controls the nuclear translocation of NPR1. NPR1 is required for the expression of not only SA-mediated defense genes, but also both morning and evening clock genes. Hence, the npr1 mutant is hypersusceptible to infection and has significantly dampened clock activities. However, how PCD is executed at the site of infection, how NPR1 inhibits PCD in distal cells and promotes SAR, and what role the circadian clock plays in regulating SAR are long- standing fundamental questions. This project will investigate how the nuclear pore complex permeability and the nuclear Ca2+ are specifically increased in executing ETI/PCD in infected cells and test the hypothesis that NPR1 reprograms the defense transcriptome and promotes survival of distal cells as a substrate adaptor for the Cul3 ubiquitin ligase complex through the formation of SA-induced NPR1 condensates in both the nucleus and the cytoplasm. The project will also determine the mechanism by which CHE is activated in systemic tissue to induce SA synthesis and explain why a clock component is involved in regulating this key step of SAR. Finally, genetic analysis will be performed to provide the molecular basis for the clock-mediated gating of the SA immune response towards the morning in avoiding plant desiccation at night and to highlight the importance of time-of-the-day chemical application in agriculture and in medicine for maximizing efficacy and reducing side effects. This continuously developing project fits the NIGMS mission of “understanding the principles, mechanisms, and processes that underlie living organisms, often using research models” and the MIRA funding model. Besides its obvious significance to basic biology and agriculture, the project may have even broader implications because SA is the oldest herbal medicine known to mankind. In recent years, aspirin (acetylated SA) has been repurposed in treating cardiovascular diseases and certain types of cancer (e.g., colon cancer). Non-acetylated SA derivatives have shown promising results in treating type II diabetes in clinical trials. However, the underlying mechanisms for these diverse medicinal effects are not completely understood and the issue over how to enhance the drug efficacy while reducing the side effect (e.g., bleeding) has to be addressed.

免疫系统的本质是确保对病原体的防御，而不会对免疫系统造成附带损害。 self.在植物中，这部分是通过调节免疫信号水杨酸（SA）来实现的。 在效应触发免疫（ETI）期间SA的产生与程序性细胞死亡相关 (PCD)以限制感染部位的病原体生长和远端细胞的存活， 广谱系统获得性抗性（SAR）。SA的这种二元函数是通过以下方式实现的： NPR 1的活动。NPR 1不仅是一种主要的免疫调节剂，而且还参与关键的细胞功能， 比如生物钟。在没有病原体攻击的情况下，SA通过细菌有节奏地产生。 直接调节时钟成分CHE，随后控制NPR 1的核转位。 NPR 1不仅是SA介导的防御基因的表达所必需的，而且也是早晨和夜间防御基因的表达所必需的。 晚钟基因因此，npr 1突变体对感染是高度敏感的，并且具有显著的 生物钟活动减弱。然而，PCD如何在感染部位执行，NPR 1如何抑制PCD 在远端细胞和促进SAR，以及昼夜节律钟在调节SAR中扮演的角色是长- 存在的基本问题。本项目将研究核孔复合体的渗透性 和细胞核Ca 2+在感染细胞中执行ETI/PCD时特异性增加，并测试 假设NPR 1重新编程防御转录组并促进远端细胞的存活， 通过形成SA诱导的NPR 1的Cul 3泛素连接酶复合物的底物衔接子 在细胞核和细胞质中浓缩。该项目还将通过以下方式确定机制： CHE在全身组织中被激活以诱导SA合成，并解释了为什么时钟成分 参与监管SAR的关键步骤。最后，将进行遗传分析以提供 SA免疫应答对早晨的时钟介导门控的分子基础， 植物干燥在夜间和强调的重要性，时间的一天中的化学应用， 农业和医药中的应用，以最大限度地提高疗效和减少副作用。这种不断发展的 该项目符合NIGMS的使命，即“理解 活生物体，通常使用研究模型”和MIRA资助模型。除了其明显的 对于基础生物学和农业的重要性，该项目可能具有更广泛的影响，因为SA是 人类已知的最古老的草药近年来，阿司匹林（乙酰化SA）已被重新利用 在治疗心血管疾病和某些类型的癌症（例如，结肠癌）。非乙酰化SA 衍生物在临床试验中显示出治疗II型糖尿病的有希望的结果。但 这些不同药物作用的潜在机制尚未完全了解， 关于如何增强药物功效同时减少副作用（例如，出血）必须解决。