Epigenetic mediated long-term aberrations in myeloid cells after critical illness

每年有超过200万美国人受到重症监护疾病（CCI）的影响， 和经济成本。CCI术后并发症的累积发病率在总死亡率中排名第4， USA. CI（例如脓毒症、创伤和心肺转流术（CPB））的共同特点是严重应激 强加于免疫系统。我们曾相信宿主的身体会恢复到受伤害前的体内平衡， 新出现的证据表明，从CI中恢复比以前认为的更快。因此，CI 幸存者遭受复发性感染（例如巨细胞病毒（CMV））和进行性器官衰竭。 在众多类型的白细胞中，单核细胞（MO）在免疫的各个方面都是关键的，但它们的功能 容易被破坏，导致无反应性、病原体/肿瘤耐受性和异常炎症。所有 这些发病率见于CCI/CPB后个体，但尚不清楚异常MO特征 是长期维持的。我们假设MO及其髓系的表观遗传调控的变化 在某些个体中，祖细胞在获得性的、长期的CCI/CPB后MO免疫畸变中是关键的。 我们的初步数据显示，约30%的CPB患者表现出MO的新获得性缺陷， 三个月的试管婴儿这种缺陷与巨噬细胞集落刺激因子的持续分泌有关 （M-CSF）CCI后和主转录因子Pu.1的表观遗传畸变。该缺陷与 炎症血清标志物（C-反应蛋白（CRP）、巨噬细胞标志物）增加，滴度升高 αCMV抗体。我们的研究计划集中在三个目标，因为它们的新奇，适用性， 现实生活中的临床状况，在未来建立富有成效的研究奋进的潜力和纠正 目标1. CPB是否会导致与PU相关的MO的持续性功能变化。1 激活目标2. CPB后MO的持续性功能变化是否通过PU的调节得以维持。1 和下游变化的表观基因组诱导PU.1结合？目标3.是持久的功能 通过PU.1的调节维持CPB后MO的变化和下游变化， PU.1结合诱导的表观基因组？ 我们的研究解决了临床上重要的问题，即CI的慢性后果和长期影响。 免疫系统调节该研究符合转化医学的当前趋势。这项建议 解决了健康维护中的关键问题，并提供了潜在的医疗干预策略。

Annually over 2 million Americans are affected by critical care illnesses (CCI), with profound societal, medical and economic costs. The cumulative morbidity from post-CCI complications ranks 4th in overall mortality in the USA. A common denominator of CI (e.g. sepsis, trauma, and cardiopulmonary bypass (CPB)) is severe stress imposed on the immune system. We had believed that the host's body returns to pre-insult homeostasis, but emerging evidence suggests that recovery from a CI is lengthier than previously thought. Consequently, CI survivors suffer from recurrent infections (e.g. cytomegalovirus (CMV)) and progressive organ failure. Among many types of leukocytes, monocytes (MO) are pivotal in all aspects of the immune yet their functions can be easily disrupted resulting in anergy, pathogen/neoplasm tolerance and aberrant inflammation. All of these morbidities are seen in post-CCI/CPB individuals but it is poorly defined how abnormal MO characteristic are maintained long-term. We hypothesize that changes in epigenetic regulation of MO and their myeloid progenitors are pivotal in an acquired, long-term post-CCI/CPB MO immuno-aberration in certain individuals. Our preliminary data shows that ~30% of CPB patients exhibit a newly acquired defect in MO that lasts at least three months in vitro. This defect is related to a persistent secretion of macrophage colony stimulating factor (M-CSF) post-CCI and epigenetic aberration of master transcription factor Pu.1. The defect correlates with increased serum markers of inflammation (C-reactive protein (CRP), macrophage markers), and elevated titers of αCMV antibodies. Our research plan focuses on three aims selected because of their novelty, applicability to real-life clinical condition, potential to build a fruitful research endeavor in a future and potential to correct the aberration Aim 1. Does CPB lead to persistent functional changes of MO associated with PU.1 activation Aim 2. Are persistent functional changes in MOs post-CPB maintained by regulation of PU.1 and downstream changes to the epigenome induced by PU.1 binding? Aim 3. Are persistent functional changes in MOs post-CPB maintained by regulation of PU.1 and downstream changes to the epigenome induced by PU.1 binding? Our study addresses clinically important questions about the chronic consequences of CI and long-term immune system regulation. The study is aligned with current trends in translational medicine. This proposal addresses a critical issue in health maintenance and provides a potential medical interventional strategy.