Cell-free DNA epigenomics to track the dynamics of organ damage and immune exhaustion during sepsis

利用游离 DNA 表观基因组学追踪脓毒症期间器官损伤和免疫衰竭的动态

• 批准号: 10274947
• 负责人: Aadel Chaudhuri
• 金额: $ 39.38万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10274947
• 关键词: Bioinformatics; Blood; Blood specimen; Cause of Death; Cells; Cessation of life; DNA analysis; DNA methylation profiling; Data; Disease; Immune; Intensive Care Units; Kinetics; Literature; Mediating; Methodology; Methods; Morbidity - disease rate; Multiple Organ Failure; Organ; Outcome; Patients; Plasma Cells; Process; Research; Sepsis; Source; State Hospitals; T-Lymphocyte; Tissues; United States; Work; cell free DNA; epigenomics; exhaust; exhaustion; genome wide methylation; improved; innovation; mortality; programs; secondary infection

PROJECT SUMMARY Sepsis is the most frequent cause of death in United States hospitals, and the number one cause of death worldwide, responsible for 11 million deaths in 2017. Primary drivers of sepsis morbidity and mortality are immune exhaustion leading to deadly secondary infection, and organ tissue damage leading to multi-organ failure. Despite the critical importance of these processes in governing ultimate sepsis outcomes, we have an incomplete understanding of their kinetics and dynamics. We thus propose a two-pronged effort to shift our paradigm regarding sepsis dynamics through plasma cell-free DNA analysis. Specifically, we propose to 1) track the dynamics of organ-specific damage, and 2) track the dynamics of T cell exhaustion during sepsis. We will do this through analysis of daily blood samples acquired from patients admitted to the intensive care unit for sepsis. Methodologically, we will achieve these through genome-wide methylation sequencing of cell-free DNA. Bioinformatically, we will then perform CIBERSORTx deconvolution to delineate and quantify specific cell/tissue types contributing to plasma cell-free DNA, thus enabling us to infer organ tissues being damaged as well as T cell exhaustion levels from both blood and tissue sources. The methods we will utilize here are highly innovative yet feasible given recent literature and our own preliminary data. Our proposed work will form the basis for a rich sepsis-focused research program utilizing cell-free DNA analysis to answer major questions in the field with the potential to ultimately improve patient survival for the deadliest disease worldwide.

项目总结