Resistin-induced immunosuppression increases susceptibility to infectious lung injury and sepsis during AKI

修改后的项目摘要/摘要 脓毒症是一个宽泛的术语，用于描述感染导致一个或多个器官系统功能障碍。最近的数据显示，脓毒症不仅仅是一个单一的实体，而是一个至少有四个亚型(或内型)的异质综合征。这些脓毒症内型表现出不同的疾病过程和结果，并且每种内型都具有独特的免疫特征。例如，在迄今发现的四种内型中，Mars1内型预后最差。它的特点是调节先天免疫和获得性免疫的关键信号成分的基因表达减少。最近的一项前瞻性研究提出了一种结合临床和遗传数据对脓毒症内型进行分子分类的方法。更好地识别不同类型的脓毒症内型不仅可以解释为什么迄今为止脓毒症的临床试验没有产生一致的有益效果，而且还可能有助于开发实用于医疗保健的诊断算法，从而满足迫切的临床需求。我们推测，抵抗素是一种新的严重败血症和感染性休克的生物标志物，可用于加强患者对不同脓毒症内型的分类。更具体地说，这项建议中要检验的假设是，腹部脓毒症发作后血液抵抗素水平的升高可以增强基于基因的模型的预测价值，这些模型预测败血症休克亚型的不良结局。这一假设是由我们强大的初步数据驱动的，这些数据表明抵抗素直接介导免疫功能障碍，并且在有最严重脓毒症后遗症的患者中升高最多。我们的长期目标是(I)了解血液抵抗素浓度如何潜在地改变脓毒症患者的治疗过程，以及(Ii)研究抵抗素在脓毒症整个过程中基于细胞的免疫调节中的机制作用。我们的具体目标是(1)通过建立有效的、人性化的腹部败血症啮齿动物模型，确定人类抵抗素在腹部败血症急性期和恢复期的作用，以及(2)结合临床数据，确定血液抵抗素浓度在预测与不良预后相关的脓毒症亚型方面的增量效用。申请者是一名强化医生，其职业目标是：(1)获得败血症临床前模型的指导经验，以及(2)获得初步数据，这些数据将指导未来作为独立临床医生-科学家的研究。申请者的指导团队包括从生理学到免疫生物学和统计遗传学的广泛研究专业知识。这项研究的目标与NIGMS的研究目标一致：识别、表征和验证脓毒症特异性生物标记物，以推进内切分型策略和未来诊断和新疗法的评估。拟议的研究方案、教学工作和指导计划将使候选人能够过渡到独立资助的内科科学家，专注于可能改变致命疾病临床管理的脓毒症内型研究。

Modified Project Summary/Abstract Sepsis is the broad term used to describe infection resulting in dysfunction of one or more organ systems. Recent data reveals that sepsis is not just a single entity, but rather a heterogeneous syndrome with at least four sub-types (or endotypes). These sepsis endotypes exhibit different disease courses and outcomes, and each is characterized by a unique immune profile. The Mars1 endotype, for example, has the worst prognosis of the four endotypes identified to date. It is typified by decreased expression of genes that regulate crucial signaling components of innate and adaptive immunity. A recent, prospective study proposed a method for the molecular classification of sepsis endotypes using a combination of clinical and genetic data. Better identification of heterogeneous sepsis endotypes may not only offer an explanation for why clinical trials for sepsis have thus far yielded no uniform beneficial effect on outcomes, but it may also help to develop diagnostic algorithms for practical use in healthcare, thus filling an urgent clinical need. We hypothesize that resistin, a novel biomarker of severe sepsis and septic shock, can be used to enhance classification of patients into different sepsis endotypes. More specifically, the hypothesis to be tested in this proposal is that elevated blood resistin levels following the onset of abdominal sepsis can enhance the predictive value of genotype- based models that prognosticate adverse outcomes in the septic shock subtype. This hypothesis is driven by our strong preliminary data which shows that resistin directly mediates immune dysfunction and is most elevated in patients having the most severe sequelae of sepsis. Our long-term goals are (i) to understand how blood resistin concentrations could potentially alter the course of management in septic patients, and (ii) to investigate resistin’s mechanistic role in cell-based immunomodulation throughout the course of sepsis. Our specific aims are to (1) determine the role of human resistin in the acute and convalescent phases of abdominal sepsis by employing a validated, humanized, rodent model of this disease, and (2) to determine the incremental utility of blood resistin concentration, when combined with clinical data, for predicting sepsis subtypes that are associated with poor outcomes. The applicant is an intensivist whose career goals are: (1) to gain mentored experience with preclinical models of sepsis, and (2) to obtain preliminary data which will guide future research as independent clinician-scientist. The applicant’s mentorship team encompasses a broad spectrum of research expertise ranging from physiology to immunobiology and statistical genetics. The goals of this study are aligned with the research objectives of the NIGMS: to identify, characterize and validate sepsis-specific biomarkers in order to advance endotyping strategies and future evaluation of diagnostics and novel therapies. The proposed research protocol, didactic work, and mentoring plan will enable the candidate transition to an independently funded physician-scientist, focusing on sepsis endotypes research which may change the clinical management of a deadly disease.