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: 10274500
• 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/10274500
• 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; Interleukin-1 beta; Knowledge; 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; macrophage; 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.

项目总结