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的助理教授Jon Wisler博士提供的一个为期五年的研究项目。本提案研究发生在败血症幸存者的表观遗传甲基化事件的机制事件和免疫抑制的临床后果。他是表观遗传调控、败血症和临床结果领域的高产研究员。该提案结合了Wisler博士在NIH K08项目期间获得的与表观遗传调控相关的知识和技能，并将其直接应用于临床和心理社会结果。败血症幸存者表现出严重程度的免疫抑制，伴有更高水平的功能衰退、抑郁、随后的感染和长期死亡率。到目前为止，与他的主题相关的调查是碎片化的，缺乏协同性。