Mechanistic Studies of Cytoplasmic dsDNA-Sensing Pathways

细胞质 dsDNA 传感途径的机制研究

基本信息

批准号：
10220074
负责人：
JUNGSAN SOHN
金额：
$ 36.21万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-20 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10220074
关键词：
Address Agonist Apoptosis Attenuated Autoimmune Diseases Autophagocytosis Base Pairing Binding Biological Assay Buffers Cell Aging Cell Death Cells Cessation of life Conflict (Psychology)Coupling Cytoplasm Data Detection Dimerization Double-Stranded RNA Equilibrium Eukaryotic Cell Future Host Defense Human Immune Immune response Immunology Inflammatory Inflammatory Response Innate Immune Response Innate Immune System Interferons Interleukin-1 beta Kinetics Length Ligand Binding Link Mammals Measurement Mediating Mitochondria Molecular Molecular Conformation N Domain Outcome Output Pathway interactions Play Positioning Attribute RNA Reagent Research Role Second Messenger Systems Shapes Signal Transduction Specificity TREX1 gene Testing Three Prime Repair Exonuclease 1 Visualization base cancer type dimer ds-DNA experimental study first responder innovation novel therapeutic intervention nuclease pathogen polymerization prevent public health relevance response sensor

项目摘要

Project summary The presence of dsDNA in the cytoplasm signals serious problems in eukaryotic cells, ranging from dysfunctional mitochondria to pathogen invasion. In mammals, the innate immune system detects these rogue dsDNA and initiate inflammatory responses. Cytoplasmic dsDNA sensing pathways are integral to host defense against numerous pathogens, and their malfunctions are also implicated in various human maladies. Here, we will define the molecular mechanisms by which cytoplasmic dsDNA sensors initiate host innate immune responses in a coordinated fashion. In Aim 1, we will resolve several controversies regarding the activation mechanism of cGAS such as why dsDNA length matters (or not), what the role of N-domain is, and how cGAS dimerizes on dsDNA. In Aim 2, we will resolve a fundamental mechanistic question in innate immunology as to what defines the dsDNA specificity of cGAS, AIM2, and IFI16. We will then test whether cellular RNA can act as a buffer to minimize the spurious activation of these sensors. In Aim 3, we will determine whether differential kinetics of cGAS, AIM2, IFI16, and the TREX1 nuclease can shape the overall host response against cytoplasmic dsDNA. We will then investigate agonism and antagonism among these sensors in generating well-balanced host responses against cytoplasmic dsDNA.

项目摘要在细胞质中存在dsDNA在真核细胞中的严重问题，从线粒体功能障碍，可导致病原体侵袭。在哺乳动物中，先天免疫系统检测到这些流氓 dsDNA并启动炎症反应。细胞质DSDNA传感途径是宿主不可或缺的对许多病原体及其故障的防御也涉及各种人类疾病。在这里，我们将定义细胞质DSDNA传感器启动宿主先天的分子机制免疫反应以协调的方式。在AIM 1中，我们将解决有关 CGA的激活机制，例如为什么DsDNA长度很重要（或不重要），n域的作用是什么以及 CGA如何在DSDNA上二聚。在AIM 2中，我们将解决先天的基本机械问题关于定义CGA，AIM2和IFI16的DSDNA特异性的免疫学。然后我们将测试是否细胞RNA可以充当缓冲液，以最大程度地减少这些传感器的虚假激活。在AIM 3中，我们将确定CGA，AIM2，IFI16和TREX1核酸酶的差异动力学是否可以塑造整体对细胞质dsDNA的宿主反应。然后，我们将研究激动和对抗传感器在产生均衡的宿主反应针对细胞质dsDNA。