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

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博士提供的五年研究计划。该提案研究了败血症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高产研究人员。该提案结合了Wisler博士在NIH K08项目中获得的与表观遗传调控相关的知识和技能，并直接应用于临床和心理社会结果。脓毒症的幸存者表现出严重的免疫抑制，功能下降、抑郁、继发感染和长期死亡率更高。迄今为止，与他的专题有关的调查是零散的，缺乏协同作用。 乔恩的研究计划旨在统一多个调查领域，以改善败血症幸存者的长期结局。他的初步数据确定，脓毒症患者在脓毒症期间表现出DNA甲基转移酶（DNMT）活性的显著增加。这导致了深刻的基因沉默和免疫抑制。此外，我们发现，外科败血症的幸存者表现出许多负面的心理社会影响，可能代表这些表观遗传介导的免疫抑制事件的临床影响。这个应用程序的目的是集成 Wisler博士的研究成果，并阐明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。我们假设，控制DNMT功能的分子或药理学手段对脓毒症患者在脓毒症后损伤的恢复期增强其先天免疫功能具有潜在益处。阐明和协调这些研究领域将大大提高我们对这些表观遗传事件的理解，并提供对机制，转化和临床结果的统一分析。在R35计划下，Jon寻求将尖端的基于实验室的调查和治疗测试与基于患者的评估相结合，包括基于时间过程的免疫功能障碍和改变的临床结果。脓毒症后免疫抑制是脓毒症存活者经常诊断但未经治疗的后果。该计划将建立时间进程，功能效应和干预途径，以治疗这种免疫抑制中涉及的潜在表观遗传事件。这将为具有显著临床影响的疾病过程产生范式转变治疗。

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.