Dysfunctional Myelopoiesis and Myeloid-Derived Suppressor Cells in Sepsis Pathobiology

脓毒症病理学中的骨髓生成功能障碍和骨髓源性抑制细胞

基本信息

批准号：
10616504
负责人：
Philip A Efron
金额：
$ 168.96万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10616504
关键词：
Acetylation Acute Address Aging Antigen-Presenting Cells Autoimmune Diseases Automobile Driving Basic Science Blood Blunt Trauma Bone Marrow Cell Respiration Cells Cessation of life Chronic Chronic Obstructive Pulmonary Disease Clinical Clinical Sciences Collaborations Critical Care Critical Illness Development Discipline Dysplasia Emergency Situation End stage renal failure Enrollment Epigenetic Process Event Exposure to Failure Generations Genes Genetic Transcription Good Clinical Practice Health Hematopoietic Hematopoietic stem cells Hospital Mortality Hospitalization Hospitals Human Immunity Immunology Immunosuppression Individual Inflammation Inflammatory Injury Intensive Care Units Kidney Diseases Leukocytes Lymphopoiesis Malignant Neoplasms Medical Metabolic Pathway Methylation Mitochondria Modernization Molecular Genetics Myeloid-derived suppressor cells Myelopoiesis Nitrogen Nutrient Operative Surgical Procedures Outcome Oxygen Paracrine Communication Pathogenesis Patients Pharmaceutical Preparations Phenotype Population Production Quality of life Research Research Personnel Resources Risk Science Secondary to Sepsis Signal Transduction Stimulus Surgical Intensive Care Syndrome T-Lymphocyte Testing Time Transcription Initiation Site Trauma Trauma patient United States Centers for Medicare and Medicaid Services adverse outcome checkpoint inhibition clinical infrastructure comorbidity conflict resolution granulocyte hematopoietic stem cell expansion high risk hospital readmission improved improved outcome meetings monocyte novel novel therapeutic intervention organizational structure patient population progenitor programs response secondary infection septic patients single-cell RNA sequencing stem cell function

项目摘要

ABSTRACT Earlier recognition of sepsis and improved implementation of best practices have significantly reduced in-hospital mortality over the past decade. As in-hospital survival has improved, the number of patients who do not fully recover has dramatically increased; nearly 50% of surgical sepsis patients will never fully recover and nearly one-third of these patients will die within 6 months. Currently, one important critical question that vexes medical practitioners is: why do some surgical sepsis patients rapidly recover while others have poor long-term outcomes despite our best supportive efforts? Why are some of our comorbid (i.e. cancer, end-stage renal disease, etc.) populations at increased risk of nonrecovery? Our overarching hypothesis is that the consequences of surgical sepsis (death and poor quality of life) are the result of an unresolving host leukocyte dyscrasia, similar to other chronic conditions such as cancer and autoimmune disease. Specifically, the preferential expansion and self-perpetuation of myeloid-derived suppressor cells (MDSCs), propagated in part through epigenetic changes in both bone marrow (BM) progenitors and MDSCs, drives non-acute infectious and noninfectious complications after sepsis. This Program will investigate in human surgical sepsis the underlying mechanisms that drive ‘dysfunctional myelopoiesis’, expansion of MDSC populations, suppressed T-cell quantities/function, and the development of patient’s immunosuppressive/inflammatory endotypes. We will primarily focus on how MDSC expansion evolves over time in surgical sepsis patients who do or do not rapidly recover; how myelopoiesis is regulated transcriptionally and epigenetically in the bone marrow of trauma patients who are at high risk of developing sepsis. There are four specific aims: Aim 1. To test the hypothesis that perpetuation of host MDSCs after acute surgical sepsis drives poor long-term clinical outcomes in surgical sepsis, including but not limited to increased secondary infections. Aim 2. To test the hypothesis that failure to recover from surgical sepsis is driven by modifiable epigenetic alterations in circulating MDSCs that induce and prolong immunosuppressive endotypes. Aim 3. To identify the distinct immunosuppressive mechanisms of MDSCs from surgical sepsis patients over time, including immunometabolism, check-point inhibition, reactive oxygen and nitrogen production, and substrate availability. Aim 4. To test the hypothesis that in response to an initial inflammatory stimulus, the increased risk of developing surgical sepsis is secondary to immunosuppression driven by a preferential bone marrow hematopoietic stem cell (HSC) expansion of MDSCs transcriptionally and epigenetically. This will be analyzed in severe blunt trauma patients at high risk for post-injury sepsis who manifest early changes in bone marrow progenitors and expansion of immunosuppressive MDSCs. Using the established clinical infrastructure of the Sepsis and Critical Illness Research Center (SCIRC), a team science approach will be employed with collaborating PI’s coming from multiple clinical and basic science disciplines. Ongoing regular biweekly meetings currently address program, resource and professional development, as well as time and effort allocation and conflict resolution.

抽象的早期对败血症和改善改善的认识有象征性医院的医院在过去的十年中，死亡率有所改善恢复急剧增加；这些患者中有三分之一将在6个月内死亡。从业者是：为什么一些手术败血症患者迅速康复，而另一些患者有池长期结局尽管我们的最佳努力？我们的总体假设的人口增加了。手术败血症（死亡和生活质量差）是一个无法解决的宿主白细胞症状的结果，类似于其他疾病，例如癌症和自身免疫性疾病。髓样衍生的抑制细胞（MDSC）的优先膨胀和自我期权，传播部分通过骨髓（BM）祖细胞和MDSC的表观遗传变化，驱动非急性败血症后的传染性和非感染性汇编将在人类手术中调查败血症，驱动“功能失调的脊髓病”的基本机制，MDSC种群的扩展，抑制T细胞的数量/功能，以及患者免疫性/炎症的发展内型。做或不迅速恢复；患有败血症的高风险的创伤患者的骨髓。宿主MDSC的垂直于急性手术败血症的假设使长期临床不良手术败血症的结局，不限于增加继发感染。假设未从手术败血症中恢复是由可修改的表观遗传改变驱动的诱导和延长免疫抑制的MDSC。随着时间的推移，包括手术败血症患者的MDSC的免疫性机制，包括免疫代谢，检查点侵蚀，活性氧和氮的产生以及底物的可用性。目的4。为了检验以下假设：响应初始炎症刺激，增加了发展的风险手术败血症是由优先骨髓造血茎驱动的免疫植物的继发的 MDSC的细胞（HSC）转录和表观遗传的膨胀。损伤后败血症的高风险患者表现出早期变化的骨髓祖细胞和膨胀使用已建立的败血症和重症疾病的临床基础设施的免疫性MDSC 研究中心（SCIRC），团队科学方法将与Pi合作的合作进行重建多个临床和基础科学的极偏见Bieekly会议当前介绍计划，资源和专业发展以及时间和精力分配和冲突解决。