Deciphering the Role of dNTP Metabolism in Innate Immunity

解读 dNTP 代谢在先天免疫中的作用

• 批准号: 10664006
• 负责人: Zhenyu Zhong
• 金额: $ 41万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-03 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10664006
• 关键词: Affect; Aging; Alzheimer' s Disease; Apoptosis; Atherosclerosis; CASP1 gene; Cells; DNA; Disease; Enzymes; Genetic; Genomic Instability; Goals; Gouty Arthritis; Homeostasis; Immune; Inflammasome; Inflammation; Inflammatory; Interleukin-1 beta; Knowledge; Macrophage; Macular degeneration; Malignant Neoplasms; Metabolic; Metabolic Pathway; Metabolism; Muscle Cells; NF-kappa B; Natural Immunity; Nuclear; Obesity; Pathogenicity; Production; Proteins; Research; Risk Factors; Role; Tissues; Virus; Virus Replication; cell growth; cell injury; cytokine; disorder risk; fitness; immune activation; immunoregulation; marenostrin; mitochondrial genome; neoplastic cell; novel therapeutics; prevent; receptor; repaired; restoration; sensor; therapy development; tissue injury; tissue repair; tripolyphosphate

Project Summary A balanced supply of deoxynucleoside triphosphates (dNTPs), the building blocks for DNA, is vital for the synthesis or repair of both nuclear and mitochondrial genomes, whereas its imbalance results in genome instability that precipitates cellular damage and breach of homeostasis. Research on dNTP metabolism has been traditionally conducted in highly proliferative (e.g. tumor cells), metabolically active (e.g. muscle cells) or virus-infected cells due to the key roles of dNTPs in fulfilling demands for cell growth, energy production and viral replication. However, little is known regarding the role of dNTP metabolism in innate immunity, especially in the context of nonpathogen-induced immune activation. A hallmark of innate immune activation is the assembly of the Nod-like receptor pyrin domain containing 3 (NLRP3) inflammasome—a dominant innate immune sensor for tissue damage. The NLRP3 inflammasome is composed of the sensor NLRP3, the adaptor ASC (apoptosis associated spike-like protein) and the effector pro-caspase-1. Assembly of the NLRP3 inflammasome proceeds with two distinct steps: ‘priming’ and ‘activation’. Priming entails rapid NF-kB activation for initiating de novo synthesis of pro-IL-1β as well as increasing the amount of NLRP3. In contrast, activation involves the assembly of the NLRP3 inflammasome machinery, resulting in autocleavage and activation of caspase-1 which then converts immature pro-IL-1β into bioactive IL-1β—a powerful proinflammatory cytokine that ignites inflammation. Although properly controlled NLRP3 inflammasome activity allows for restoration of homeostasis after traumatic tissue injury by stimulating damage clearance and tissue repair, its aberrant and prolonged activation also promotes the rapid progression of many devastating disorders, including gouty arthritis, Alzheimer’s disease, atherosclerosis, macular degeneration and cancer. It is therefore crucial to understand how NLRP3 inflammasome activity is regulated in innate immune cells. Recently, we discovered that genetic deletion of CMPK2 or SAMHD1, two key enzymes within the dNTP metabolic pathways responsible for synthesizing or degrading dNTPs respectively, orchestrates NLRP3 inflammasome activation. Therefore, the ultimate goal of this MIRA R35 project is to establish dNTP metabolism as a new layer for innate immune regulation and further delineate its underlying mechanism of action. To achieve this goal, three major scientific questions will be pursued: (1) how does inflammasome priming regulate the function of dNTP metabolic enzymes? (2) how does dNTP metabolism control NLRP3 inflammasome activation? Lastly, since NLRP3 inflammasome overactivation is a shared pathogenic hallmark of many diseases, we further asked: (3) do common disease risk factors, such as aging and obesity, dysregulate macrophage dNTP metabolism, thereby permitting NLRP3 inflammasome overactivation? Completion of this project will not only fill an important knowledge gap in the innate immunity field, but may also guide new therapy development to prevent NLRP3 inflammasome hyperactivation.

项目摘要 脱氧核苷三磷酸（DNTP）的平衡供应，DNA的构建块，对于 核和线粒体基因组的合成或修复，而其不平衡导致基因组 不稳定会导致细胞损伤并破坏体内稳态。 DNTP代谢的研究有 传统上是在高度增殖（例如肿瘤细胞），代谢活性（例如肌肉细胞）或 由于DNTP的关键作用在满足细胞生长，能量生产和 病毒复制。但是，关于DNTP代谢在先天免疫中的作用，尤其是知之甚少 在非病原体诱导的免疫激活的背景下。先天免疫激活的标志是 含有3（NLRP3）炎症体的点头样受体吡啶结构域的组装 - 主要先天 免疫传感器可用于组织损伤。 NLRP3炎症组由传感器NLRP3组成 ASC（凋亡与尖峰样蛋白相关）和效应子pro-caspase-1。 NLRP3的组装 炎症小组以两个不同的步骤进行：“启动”和“激活”。启动需要快速的NF-KB 激活启动pro-IL-1β的从头合成以及增加NLRP3的量。相比之下， 激活涉及NLRP3炎性体机械的组装，从而导致自cleavage和 caspase-1的激活然后将未成熟的pro-IL-1β转化为生物活性IL-1β 促炎细胞因子点燃感染。虽然适当控制的NLRP3炎性体活动 通过刺激损伤清除和组织，可以在创伤组织损伤后恢复体内平衡 维修，其异常和延长激活也促进了许多毁灭性的快速发展 疾病，包括盖蒂关节炎，阿尔茨海默氏病，动脉粥样硬化，黄斑变性和癌症。它 因此，了解如何在先天免疫细胞中调节NLRP3炎性体活动至关重要。 最近，我们发现CMPK2或SAMHD1的遗传缺失，DNTP中的两个关键酶 负责合成或降解DNTP的代谢途径，编排NLRP3 炎症体激活。因此，这个MIRA R35项目的最终目标是建立DNTP 代谢作为先天免疫调节的新层，并进一步描述了其基本机制 行动。为了实现这一目标，将提出三个主要的科学问题：（1）炎症如何如何 启动调节DNTP代谢酶的功能？ （2）DNTP代谢控制NLRP3如何 炎性体激活？最后，由于NLRP3炎性体过度活化是一种共享的致病标志 在许多疾病中，我们进一步问：（3）做常见的疾病危险因素，例如衰老和肥胖症， 失调的巨噬细胞DNTP代谢，从而允许NLRP3炎性体过度活化？ 该项目的完成不仅会填补先天免疫领域的重要知识差距，还可以 还指导新的疗法开发，以防止NLRP3炎性体过度激活。