Functions of novel phospholipase D proteins in nucleic acid sensing

新型磷脂酶 D 蛋白在核酸传感中的功能

基本信息

批准号：
10405523
负责人：
DAVID NEMAZEE
金额：
$ 48.38万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-14 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10405523
关键词：
Affect Agonist Alzheimer&apos s Disease Antigen-Presenting Cells Automobile Driving Biochemical Biology Cells Chronic Crystallization DNA Data Dendritic Cells Deoxyribonucleases Development Discrimination Disease Enzymes Exonuclease Future Goals Host Defense Human Inflammation Ingestion Injections Interferon Type I Knock-out Leukocytes Ligands Link Lymphocytic choriomeningitis virus Macrophage activation syndrome Microbe Mus Nature Nucleic Acids Nucleosides Oligonucleotides Pathogenicity Pathway interactions Pattern Phenotype Phospholipase Phospholipase D Production Proteins RNA RNA Degradation RNA Viruses Resistance Rheumatism Rheumatoid Arthritis Role Structure Substrate Specificity Systemic Scleroderma TLR7 gene TLR8 gene TLR9 gene Testing Therapeutic Translational Research Variant Virus autoinflammatory cell type comparative cytokine delta protein familial hemophagocytic lymphohistiocytosis genome wide association study human disease influenzavirus lysosomal proteins microorganism novel response sensor transcriptome sequencing tumor viral resistance

Affect Agonist Alzheimer&apos s Disease Antigen-Presenting Cells Automobile Driving Biochemical Biology Cells Chronic Crystallization DNA Data Dendritic Cells Deoxyribonucleases Development Discrimination Disease Enzymes Exonuclease Future Goals Host Defense Human Inflammation Ingestion Injections Interferon Type I Knock-out Leukocytes Ligands Link Lymphocytic choriomeningitis virus Macrophage activation syndrome Microbe Mus Nature Nucleic Acids Nucleosides Oligonucleotides Pathogenicity Pathway interactions Pattern Phenotype Phospholipase Phospholipase D Production Proteins RNA RNA Degradation RNA Viruses Resistance Rheumatism Rheumatoid Arthritis Role Structure Substrate Specificity Systemic Scleroderma TLR7 gene TLR8 gene TLR9 gene Testing Therapeutic Translational Research Variant Virus autoinflammatory cell type comparative cytokine delta protein familial hemophagocytic lymphohistiocytosis genome wide association study human disease influenzavirus lysosomal proteins microorganism novel response sensor transcriptome sequencing tumor viral resistance

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项目摘要

Project Summary/Abstract This is a R01 project to study the role of Phospholipase D4 (PLD4) in nucleic acid sensing. Leukocytes carry conserved sensors for endocytosed DNA and RNA that trigger the production of proinflammatory cytokines, including type I interferon. The ensuing inflammation can be beneficial for host defense to microorganisms, viruses, and tumors, but can also be pathogenic, and may thwart the use of potentially therapeutic oligonucleotides. PLD4 is a lysosomal protein whose function is not understood. Genome-wide association studies have linked PLD4 to human rheumatoid arthritis and systemic sclerosis. We find that PLD4-deficient mice have a phenotype similar to the human disease macrophage activation syndrome, which is mimicked in mice by repeated injections with Toll-like receptor 9 agonists. Here we test the hypotheses that PLD4 breaks down ingested DNA and RNA and regulates host defense and inflammation by promoting the destruction nucleic acids and regulating recognition by TLR7, TLR8 (in humans) and TLR9. We will characterize how PLD4 deficiency promotes a MAS-like phenotype and how deficiencies in PLD4 or PLD3+PLD4 affect TLR7 and TLR9 responses to specific ligands, leading to altered cytokine secretion. The possible role of PLD4 in self/nonself discrimination will also be assessed. The long-term goal of these studies is to understand the basic biology of PLD4, its functions in host defense and inflammation, and to develop a basis for potential future translational research.

项目摘要/摘要这是一个R01项目，用于研究磷脂酶D4（PLD4）在核酸传感中的作用。白细胞携带保守的传感器，用于触发促炎性产生的内吞DNA和RNA 细胞因子，包括I型干扰素。随之而来的炎症可能对宿主防御有益微生物，病毒和肿瘤，但也可能是致病性的，可能会阻止使用潜在的治疗性寡核苷酸。 PLD4是一种溶酶体蛋白，其功能不了解。全基因组协会研究将PLD4与人类类风湿关节炎和全身性硬化联系起来。我们发现 PLD4缺陷小鼠的表型与人类疾病巨噬细胞激活综合征相似，通过反复注射Toll样受体9激动剂在小鼠中模仿小鼠。在这里我们测试 PLD4分解摄入的DNA和RNA并调节宿主防御和炎症的假设通过促进破坏核酸并调节TLR7，TLR8（人类）和 TLR9。我们将表征PLD4缺乏症如何促进类似MAS的表型以及如何缺乏 PLD4或PLD3+PLD4影响TLR7和TLR9对特定配体的反应，导致细胞因子改变分泌。还将评估PLD4在自我/非自我歧视中的可能作用。长期目标这些研究是了解PLD4的基本生物学，其在宿主防御和炎症中的功能，并为潜在的未来翻译研究开发基础。