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

修改后的项目摘要/摘要 脓毒症是用于描述导致一个或多个器官系统功能障碍的感染的广义术语。最近的数据表明，脓毒症不仅仅是一个单一的实体，而是一个异质性综合征，至少有四个亚型（或内型）。这些脓毒症内源型表现出不同的疾病过程和结果，并且每种都以独特的免疫特征为特征。例如，Mars 1内型在迄今为止鉴定的四种内型中具有最差的预后。其典型表现为调节先天性和适应性免疫的关键信号组分的基因表达降低。最近的一项前瞻性研究提出了一种结合临床和遗传学数据对脓毒症内型进行分子分类的方法。更好地识别异质性脓毒症内型不仅可以解释为什么脓毒症的临床试验迄今为止对结果没有产生统一的有益效果，而且还可以帮助开发用于医疗保健的诊断算法，从而满足迫切的临床需求。我们假设，一种新的严重脓毒症和脓毒性休克的生物标志物，可用于加强对不同脓毒症内型患者的分类。更具体地说，在该提议中待检验的假设是，在腹部脓毒症发作后升高的血液β-葡聚糖水平可以增强基于基因型的模型的预测价值，该模型预测脓毒性休克亚型中的不良结果。这一假设是由我们强有力的初步数据驱动的，这些数据表明，BcN直接介导免疫功能障碍，并且在具有最严重败血症后遗症的患者中最高。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）研究抵抗素在整个脓毒症过程中在细胞免疫调节中的机制作用。我们的具体目标是：（1）通过采用经验证的人源化啮齿动物腹腔脓毒症模型，确定人β-内酰胺酶在腹腔脓毒症急性期和恢复期的作用;（2）确定血液β-内酰胺酶浓度与临床数据相结合时的增量效用，用于预测与不良结局相关的脓毒症亚型。申请人是一名重症监护医师，其职业目标是：（1）获得脓毒症临床前模型的指导经验，以及（2）获得初步数据，以指导未来作为独立临床医生-科学家的研究。申请人的导师团队包括广泛的研究专业知识，从生理学到免疫生物学和统计遗传学。本研究的目标与NIGMS的研究目标一致：鉴定、表征和验证脓毒症特异性生物标志物，以推进内分型策略和未来诊断和新疗法的评价。拟议的研究方案，教学工作和指导计划将使候选人过渡到一个独立资助的医生，科学家，专注于脓毒症内型研究，这可能会改变致命疾病的临床管理。

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.