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

这项建议是针对Jon Wisler博士的一个为期五年的研究计划，Jon Wisler博士是创伤、重症监护和烧伤外科的助理教授。这项建议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。威斯勒博士在表观遗传调控、败血症和临床结果领域是一位高产的研究人员。这项建议将威斯勒博士在NIH K08项目中获得的与表观遗传调控相关的知识和技能与临床和心理社会结果的直接应用结合起来。脓毒症的幸存者表现出严重的免疫抑制，功能衰退、抑郁、继发感染和长期死亡率更高。到目前为止，与他的话题相关的调查是零散的，缺乏协同效应。 乔恩的研究计划寻求统一多个调查领域，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DNA甲基转移酶(DNMT)活性显著增加。这导致了严重的基因沉默和免疫抑制。此外，我们发现外科脓毒症的幸存者表现出许多负面的心理社会效应，这可能代表了这些表观遗传介导的免疫抑制事件的临床效应。这个应用程序的目的是将 Wisler博士的研究努力，并阐明这些表观遗传事件的有害生物、心理和社会后果，以及对纵向免疫功能和恢复的体内评估。我们推测，控制DNMT功能的分子或药物手段对脓毒症患者在败血症后侮辱恢复期提高他们的天然免疫功能具有潜在的好处。整合和协调这些研究领域将极大地提高我们对这些表观遗传事件的理解，并提供对机制、翻译和临床结果的统一分析。在R35计划下，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改变的临床结果。脓毒症后免疫抑制是脓毒症存活的一个经常被诊断但未治疗的后果。该计划将确定治疗这种免疫抑制所涉及的潜在表观遗传学事件的时间进程、功能效应和干预途径。这将为具有重大临床影响的疾病过程产生范式转换治疗。

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.