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

• 批准号: 10088857
• 负责人: Philip A Efron
• 金额: $ 152.79万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 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/10088857
• 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 Airway Disease; Clinical; Clinical Sciences; 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; Hospitals; Human; Immunity; Immunology; Immunosuppression; Individual; Inflammation; Inflammatory; Injury; Intensive Care Units; Kidney Diseases; Lead; 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; Play; Population; Production; Quality of life; Research; Research Personnel; Resources; Risk; Role; 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

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.

摘要 早期认识脓毒症和改善最佳实践的实施，大大减少了住院 死亡率在过去十年。随着住院存活率的提高， 康复率急剧增加;近50%的外科脓毒症患者将永远不会完全康复， 三分之一的患者会在6个月内死亡。目前，困扰医学界的一个重要关键问题是， 为什么一些外科脓毒症患者迅速恢复，而另一些患者的长期结果很差？ 尽管我们尽了最大的努力为什么我们的一些共病（即癌症，终末期肾病等） 不恢复风险增加的人群？我们的首要假设是， 外科败血症（死亡和生活质量差）是未消退的宿主白细胞恶液质的结果， 与癌症和自身免疫性疾病等其他慢性病类似。具体而言是 骨髓来源的抑制细胞（MDSC）的优先扩增和自我永存， 部分通过骨髓（BM）祖细胞和MDSC中的表观遗传变化， 脓毒症后感染性和非感染性并发症。该计划将研究人类外科手术 脓毒症驱动“功能障碍性骨髓生成”的潜在机制，MDSC群体的扩张， 抑制T细胞数量/功能，以及患者免疫抑制/炎症的发展 内型我们将主要关注MDSC扩张如何在外科脓毒症患者中随时间演变， 是否迅速恢复;骨髓生成如何在骨中转录和表观遗传调节 创伤患者的骨髓，这些患者处于发展脓毒症的高风险中。有四个具体目标：目标1。测试 急性外科脓毒症后宿主MDSC的永久存在导致不良的长期临床 手术脓毒症的结局，包括但不限于继发性感染增加。目标2.测试 不能从手术脓毒症中恢复是由循环中可修饰的表观遗传改变驱动的假设 诱导和延长免疫抑制性内型的MDSC。目标3.要识别不同的 随着时间的推移，来自外科败血症患者的MDSC的免疫抑制机制，包括 免疫代谢、检查点抑制、活性氧和氮产生以及底物可用性。 目标4。为了验证这一假设，即在对初始炎症刺激的反应中， 外科败血症继发于由优先骨髓造血干细胞驱动的免疫抑制 细胞（HSC）扩增的MDSC的转录和表观遗传。这将在严重的钝性创伤中进行分析 表现出骨髓祖细胞和扩增早期变化的损伤后脓毒症高危患者 免疫抑制MDSC。利用已建立的脓毒症和危重病临床基础设施， 研究中心（SCIRC），将采用团队科学方法，与来自 多个临床和基础科学学科。正在进行的定期双周会议目前解决方案， 资源和专业发展，以及时间和精力的分配和冲突的解决。