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Conserved Immune Response to Sensing Cytosolic DNA

对感测胞质 DNA 的保守免疫反应

基本信息

批准号：
8900923
负责人：
Alan Gabriel Goodman
金额：
$ 24.9万
依托单位：
WASHINGTON STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8900923
关键词：
Address Affect American Animal Model Animals Autoimmune Diseases Autoimmune Process Autoimmunity Award Bacterial Infections Binding Biochemical Biological Models Biomedical Engineering Birth Cardiovascular system Cells Chronic Collaborations Complement Computing Methodologies DNA Data Disease Double-Stranded RNA Drosophila Proteins Drosophila genus Drosophila melanogaster Environment Equipment Event Exhibits Exposure to Faculty Fat Body Gene Activation Gene Expression Genes Genomic Library Genomics Goals Hemolymph Homologous Gene Host Defense Human Immune Immune response Immune system Immunology Infection Inflammatory Interferon-beta Interferons Invaded Knock-out Knowledge Life Cycle Stages Ligands Malignant Neoplasms Mammals Maps Mentors Mentorship Microbiology Microscopy Modeling Molecular Molecular Biology Natural Immunity Nerve Degeneration Nuclear Translocation Nucleic Acid Binding Nucleic Acids Organism Outcome Pathogen detection Pathology Pathway interactions Phase Postdoctoral Fellow Process Proteins RNA Interference Reaction Receptor Activation Receptor Signaling Research Research Personnel Role Signal Pathway Signal Transduction Site Specificity Surface System Techniques Testing Therapeutic Intervention Training Transgenic Organisms Universities Viral Viral Genome Virus Diseases Work abstracting antimicrobial antimicrobial peptide base bone career design fly gene function grasp human disease improved insight loss of function microbial mutant next generation sequencing novel pathogen peptidoglycan recognition protein receptor response sensor signature molecule therapeutic development therapeutic target therapy development transcription factor vaccine development viral RNA virology

项目摘要

Conserved Immune Response to Sensing Cytosolic DNA Project Summary/Abstract: Candidate: Throughout my scientific career I have been involved in the study of host-pathogen interactions, with an emphasis on bioengineering, microbiology, immunology, and vaccine development. Training in virology, molecular biology, and computational methods has helped me answer a wide variety of scientific questions. The project proposed here is designed to bridge my transition from a postdoctoral fellow to an independent investigator in an academic setting to continue my pursuit of using creative approaches to high- impact, adventurous research to understand the host response to pathogenic infection. Research: Innate immunity refers to the body's initial response to curb infection upon exposure to invading organisms. While the detection of pathogen-associated molecules is an ancient form of host defense, if dysfunctional, it can cause autoimmune disease, which affects over 20 million Americans. The innate immune response is the first line of defense to microbial infection, and it is initiated through the activation of receptors recognizing conserved molecules that are signature of pathogenic infection. Recently, STING (STimulator of INterferon Genes), an intracellular sensor of cytosolic DNA was discovered. STING is critical to the innate immune response during viral and bacterial infection, yet animals exhibiting STING hyperactivation at birth display inflammatory autoimmune disease. While the downstream signaling events occurring after STING activation are well understood, little is known about the mechanisms responsible for STING activation. To address this question, I propose an orthogonal approach utilizing Drosophila melanogaster to investigate STING function and the molecules that stimulate it. This approach will complement the ongoing studies of STING in a mammalian system. In Aim 1, we will determine how human STING and Drosophila STING (dSTING) are similar, providing evidence that dSTING is the bone fide ancestor of human STING. We will assess the capacity of dSTING to bind nucleic acids and characterize the domains of dSTING to determine which are critical for nucleic acid binding and intracellular localization. In Aim 2, we will create a dSTING knockout fly to study the role of dSTING in the innate immune response to infection. Gene expression analyses will be used to functionally determine how the loss of dSTING contributes to an impaired innate immune response, as compared to that of a genomic rescue fly. Aim 3 will utilize next-generation sequencing to identify the nucleic acids that bind to dSTING during microbial infection, providing insight to the specificity of the ligand for STING, a site for potential therapeutic intervention. Together, these studies using the genetically malleable Drosophila model system will improve our understanding of STING function through the extrapolation of the results into the mammalian system for further experimentation. The information gained in this study will have broad-ranging impacts in innate and autoimmunity towards to the development of therapeutics to treat microbial infection and autoimmune disorders. Environment: This project complements the ongoing research on innate immunity of my proposed mentor, Dr. Glen Barber. The work will also setup new collaborations with my co-mentor, Dr. Grace Zhai. Both mentors will provide invaluable mentorship throughout the K99 phase of the award, giving me the training necessary for the rise to independence. The University of Miami has superb facilities, equipment, and outstanding faculty who study microbiology and immunology, through the use of exciting techniques and animal models.

敏感胞质DNA的保守免疫反应