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.

该建议是针对创伤，重症监护和烧伤手术部助理教授乔恩·威斯勒（Jon Wisler）博士进行的五年研究计划。该建议研究了败血症幸存者发生的表观遗传甲基化事件的机械事件和免疫抑制临床后果。 Wisler博士是表观遗传调节，败血症和临床结果领域的高产研究人员。该建议将Wisler博士的NIH K08计划中获得的知识和技能融合了与表观遗传调节有关的知识和技能，并直接适用于临床和心理社会成果。败血症的幸存者表现出深度的免疫抑制，功能下降，抑郁，随后的感染和长期死亡率较高。迄今为止，与他的话题有关的调查是分散的，缺乏协同作用。 乔恩（Jon）的研究计划旨在统一多个投资领域，以改善败血症的长期结果。他的初步数据表明，败血症患者在败血症期间暴露了DNA甲基转移酶（DNMT）活性的显着增加。这导致了深刻的基因沉默和免疫抑制。此外，我们表明，手术败血症的幸存者暴露了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作用。我们对此应用的目的是集成 Wisler博士的研究工作，并阐明了这些表观遗传事件的已删除的生物心理社会后果，并在体内评估纵向免疫功能和恢复。我们假设控制DNMT功能的分子或药物手段对败血症患者具有潜在的益处，可以在癫痫后侮辱的恢复阶段促进其先天免疫功能。结合和协调这些研究领域将大大改善我们的R35计划，乔恩试图将基于最先进的实验室的研究和治疗测试与基于患者的评估（包括基于时间课程的免疫功能障碍和改变的临床结果）相结合。 sepsis后免疫抑制是败血症生存的经常被诊断但未经治疗的结果。该计划将建立时间过程，功能效应以及干预措施的途径，以治疗这种免疫抑制所涉及的潜在表观遗传事件。这将为具有重大临床影响的疾病过程产生范式转移治疗。