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Human Immunomics & Trained Immunity in Persistent Candidemia

人类免疫组学

基本信息

批准号：
10551710
负责人：
ELAINE F REED
金额：
$ 43.61万
依托单位：
LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-10 至 2028-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10551710
关键词：
ATAC-seq Address Affect Anti-Infective Agents Antibiotic Therapy Antibiotics Antifungal Therapy Antigen Presentation Attenuated Automobile Driving Big Data Biological Assay Biometry Blood specimen Candida albicans Candidiasis ChIP-seq Chromatin Clinical Clinical Research Coculture Techniques Communicable Diseases Computer Analysis Computer Models DNA Methylation Data Disease Outcome Disseminated candidiasis Enhancers Enzymes Epigenetic Process Experimental Models Genetic Genetic Transcription Goals Hematogenous Hematology Histone Acetylation Hospitals Human Immune Immune Response Genes Immune response Immune system Immunity Immunology In Vitro Infection Innate Immune Response Integration Host Factors Interferon Type II Interferon alpha Intervention Life Link Macrophage Maps Mediating Methicillin Resistance Modification Molecular Multi-Drug Resistance Mus Myeloid Cells Natural Immunity Nitrous Oxide Outcome Oxygen Pathologic Pathway interactions Patients Peripheral Phagocytosis Plasma Prophylactic treatment Proteomics Research Role Sepsis Shapes Signal Pathway Signal Transduction Specificity Staphylococcus aureus Staphylococcus aureus infection Stimulus Sulfides Surface System Systems Biology T cell response T-Cell Activation T-Lymphocyte TNF gene Training Vaccines Validation adaptive immune response adaptive immunity beta-Glucans candidemia cathelicidin antimicrobial peptide chemokine chronic infection cytokine diagnostic tool epigenome epigenomic profiling epigenomics histone methylation immune function in vivo infection rate inhibitor innate immune function innovation insight machine learning model methylation pattern mortality multiple omics mutant network models novel pathogen peripheral blood pharmacologic predictive modeling predictive signature programs promoter prophylactic resistant strain response statistical learning survival outcome targeted treatment therapeutic development therapeutic target transcription factor transcriptome transcriptome sequencing transcriptomics whole genome

项目摘要

PROJECT SUMMARY Hematologic disseminated candidiasis (HDC) is the most common invasive fungal species in hospital settings worldwide. The mortality rate is high (40%) for these infections despite treatment with antifungal therapies. Similarly, methicillin-resistant strains of Staphylococcus aureus (MRSA) can cause invasive and life-threatening infections despite treatment with standard anti-infective therapies. Thus, persistence reflects host-pathogen interactions occurring uniquely in context of antibiotic therapy in vivo. However, host factors and mechanisms involved in persistent MRSA and HDC remain unclear. This study will use systems-based, high-throughput multi-omics platforms and novel statistical and computational approaches to provide a comprehensive longitudinal assessment of host in vitro and in vivo innate and adaptive responses to HDC and MRSA infection using patient peripheral blood, stimulus specific PAMPs and patient-derived HDC plasma PAMPs and isolates. Innovative deliverables include: i) Constructing an in-depth immune profile of HDC and MRSA immune profiles; ii) understand the stimulus-specificity of de novo enhancer formation in macrophages and how they affect transcriptional landscapes and functions iii) generate a detailed molecular map of the cross-talk between the innate and adaptive immune response during HDC and MRSA infection; iv) using the combination of biostatistics and computational modeling to explain and predict cellular and molecular networks driving trained immunity and persistent, resolving, and survival outcomes; and v) identification and validation of druggable epigenomic regulators of reprogramming. Detailed insights into the interaction of HDC and MRSA with the host immune system stand to generate fundamentally new mechanistic hypotheses and diagnostic tools to guide development of therapeutic strategies.

项目总结