Analyzing the long-term effects of DNA methylation meditated immunosuppression following sepsis

分析败血症后 DNA 甲基化介导的免疫抑制的长期影响

• 批准号: 10714859
• 负责人: Jon R Wisler
• 金额: $ 39.38万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-10 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10714859
• 关键词: Area; Clinical; Clinical Investigator Award; Coupled; Couples; Critical Care; DNA Methylation; DNA Modification Methylases; Data; Diagnosis; Disease; Epigenetic Process; Event; Exhibits; Gene Silencing; Immune System Diseases; Immunologics; Immunosuppression; In Vitro; Infection; Intervention; Investigation; Knowledge; Laboratories; Long-Term Effects; Mediating; Meditation; Mental Depression; Methylation; Molecular; Operative Surgical Procedures; Outcome; Outcome Measure; Patient-Focused Outcomes; Patients; Phase; Process; Productivity; Quality of life; Recovery; Regulation; Research; Research Personnel; Sepsis; Survivors; Time; Trauma; Treatment/Psychosocial Effects; United States National Institutes of Health; biopsychosocial; clinical effect; direct application; disability; epigenetic regulation; functional decline; functional outcomes; human data; immune function; improved; in vivo; innate immune function; insight; mortality; novel therapeutics; pharmacologic; professor; programs; psychosocial; response; restoration; septic; skills; survivorship; synergism; therapeutic evaluation

This proposal is for a five-year research program for Dr. Jon Wisler, an Assistant Professor in the Division of Trauma, Critical Care, and Burn Surgery. This proposal studies the mechanistic events and immunosuppressive clinical consequences of epigenetic methylation events that occur in survivors of sepsis. Dr. Wisler is a highly productive researcher in the fields of epigenetic regulation, sepsis, and clinical outcomes. This proposal couples the knowledge and skills gained during Dr. Wisler’s NIH K08 program relating to epigenetic regulation with direct application to clinical and psycho-social outcomes. Survivors of sepsis exhibit a profound degree of immunosuppression with higher levels of functional decline, depression, subsequent infections, and long-term mortality. To date, investigations related to his topic are fragmented and lack synergy. Jon’s research program seeks to unify multiple areas of investigation to improve the long-term outcomes of survivors of sepsis. His preliminary data identifies that patients with sepsis exhibit significant increases in DNA methyltransferase (DNMT) activity during sepsis. This results in profound gene silencing and immunosuppression. Additionally, we show that survivors of surgical sepsis exhibit numerous negative psycho-social effects that may represent the clinical effects of these epigenetically mediated immunosuppression events. Our intent for this application is to integrate the research efforts of Dr. Wisler and elucidate the deleterious biopsychosocial consequences of these epigenetic events coupled with in vivo assessments of longitudinal immune function and restoration. We hypothesize that molecular or pharmacological means to control DNMT function has potential benefits to patients with sepsis for boosting their innate immune function during the recovery phase of post-septic insult. Incorporating and coordinating these areas of research will greatly improve our understanding of these epigenetic events and provide a unified analysis of mechanistic, translational, and clinical outcomes. Under the R35 program, Jon seeks to integrate cutting-edge laboratory-based investigations and therapeutic testing with patient-based assessments including time-course based immunologic dysfunction and altered clinical outcomes. Post-sepsis immunosuppression is an often diagnosed but untreated consequence of sepsis survivorship. This program will establish the time course, functional effects, and avenues of interventions to treat the underlying epigenetic events involved in this immunosuppression. This will generate paradigm shifting treatments for a disease process with significant clinical impact.

该提案是为创伤、重症监护和烧伤外科部门的助理教授 Jon Wisler 博士开展的一项为期五年的研究计划，该提案研究幸存者中发生的表观遗传甲基化事件的机制事件和免疫抑制临床后果。 Wisler 博士是表观遗传调控、脓毒症和临床结果领域的一位高效的研究人员，该提案结合了 Wisler 博士在 NIH K08 项目中获得的与表观遗传学相关的知识和技能。脓毒症幸存者表现出严重的免疫抑制，伴有更高水平的功能衰退、抑郁、后续感染和长期死亡率。缺乏协同作用。 Jon 的研究项目旨在统一多个领域的研究，以改善脓毒症幸存者的长期结果。他的初步数据表明，脓毒症患者在脓毒症期间表现出 DNA 甲基转移酶 (DNMT) 活性显着增加，这导致了严重的基因沉默。免疫抑制。我们发现手术脓毒症的幸存者表现出许多负面的心理社会影响，这可能代表了这些表观遗传介导的免疫抑制事件的临床影响。我们的目的是额外整合这些表观遗传介导的免疫抑制事件。 Wisler 博士的研究成果阐明了这些表观遗传事件的有害生物心理社会后果，再加上纵向免疫功能和恢复的体内评估，我们发现控制 DNMT 功能的分子或药理学方法对脓毒症患者具有潜在的益处，可以增强其先天性。合并和协调这些领域的研究将极大地提高我们对这些表观遗传事件的理解，并提供机制、转化和临床的统一分析。根据 R35 计划，Jon 寻求将基于实验室的尖端研究和治疗测试与基于患者的评估相结合，包括基于时间进程的免疫功能障碍和脓毒症后免疫抑制的改变，这是脓毒症后经常被诊断但未经治疗的后果。该计划将确定治疗这种免疫抑制所涉及的潜在表观遗传事件的时间进程、功能效应和途径，这将为具有重大临床影响的疾病过程带来范式转变的治疗方法。