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

抵抗素诱导的免疫抑制增加 AKI 期间感染性肺损伤和脓毒症的易感性

• 批准号: 10213099
• 负责人: Anthony S Bonavia
• 金额: $ 20.16万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10213099
• 关键词: Abdomen; Acute; Affect; Algorithms; Amino Acid Sequence Homology; Antibiotics; Bacteria; Biochemical; Biological Markers; Blood; Blood specimen; C57BL/6 Mouse; Cells; Cessation of life; Classification; Clinical; Clinical Data; Clinical Management; Clinical Trials; Computer Models; Control Groups; Convalescence; Critical Illness; Data; Diagnostic; Disease; Disease model; Evaluation; Excision; Exhibits; Functional disorder; Funding; Future; Gene Expression; Genes; Genetic; Genotype; Goals; Healthcare; Human; Immune; Immune System Diseases; Immunobiology; Immunocompromised Host; Immunosuppression; Impairment; In Vitro; Infection; Inflammation; Knock-in; Link; Mediating; Mediator of activation protein; Medical Genetics; Mentors; Mentorship; Methods; Modality; Modeling; Molecular; Monitor; Multivariate Analysis; Mus; National Institute of General Medical Sciences; Natural Immunity; Outcome; Patients; Peritonitis; Phase; Phenotype; Physicians; Physiological; Physiology; Plasma; Pre-Clinical Model; Predictive Value; Predisposition; Production; Prognosis; Prognostic Marker; Promoter Regions; Prospective Studies; Protocols documentation; Publishing; Reactive Oxygen Species; Recovery; Research; Rodent Model; Role; Sampling; Scientist; Sepsis; Septic Shock; Severities; Signal Transduction; Source; Syndrome; Testing; Therapeutic; Therapeutic Intervention; Transgenic Mice; Work; adaptive immunity; adverse outcome; base; body system; career; cecal ligation puncture; cell motility; cytokine; diagnostic biomarker; experience; extracellular; fighting; immunoregulation; in vivo; lung injury; macrophage; monocyte; mortality; mouse model; neutrophil; novel; novel marker; novel therapeutics; outcome prediction; prognostic; promoter; prospective; resistin; response; septic; septic patients; specific biomarkers

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.

修改的项目摘要/摘要 败血症是用于描述感染的广义术语，导致一个或多个器官系统功能障碍。最近的数据表明，败血症不仅是一个实体，而且是一种至少四个亚型（或内型）的异质综合征。这些败血症内型暴露了不同的疾病课程和结果，每种疾病的特征都具有独特的免疫特征。例如，MARS1内型具有迄今为止确定的四种内型的预后最差。它的代表是调节先天和适应性免疫学的关键信号成分的基因的高级表达。最近的一项前瞻性研究提出了一种使用临床和遗传数据组合的败血症内型分子分类的方法。更好地识别异质性败血症内型不仅可以解释为什么败血症的临床试验对结局没有统一的有益作用，而且还可能有助于开发用于医疗保健的诊断算法，从而满足紧急临床需求。我们假设抗蛋白是一种新型的严重败血症和败血性休克的生物标志物，可用于将患者分类为不同的败血症内型。更具体地说，在该提案中要检验的假设是，腹部败血症开始后的血液抵抗水平升高可以增强基于基因型模型的预测值，这些模型证明了败血性休克亚型中的不良结果。该假设是由我们强大的初步数据驱动的，该数据表明，抵抗素直接介导免疫功能，并且在患有败血症后遗症最严重的患者中升高。我们的长期目标是（i）了解抗败血症患者的血液抗性浓度如何可能改变治疗过程，以及（ii）在整个败血症过程中研究阻力蛋白在基于细胞的免疫调节中的机械作用。我们的具体目的是（1）通过采用经过验证的，人性化的，人源化的啮齿动物模型来确定人类抗性在腹部败血症的急性和恢复阶段的作用，以及（2）确定与临床数据相结合的血液抵抗浓度的增量，以预测与贫困相关的败血症亚型相关的败血症。申请人是一个强化主义者，其职业目标是：（1）获得败血症临床前模型的指导经验，（2）获得初步数据，将指导未来的研究作为独立的临床科学家。申请人的心态团队涵盖了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NIGM的研究目标保持一致：识别，表征和验证败血症特异性生物标志物，以提高内型策略以及对诊断和新疗法的未来评估。拟议的研究方案，教学工作和心理计划将使候选人过渡到独立资助的身体科学家，重点是败血症内型研究，这可能会改变致命疾病的临床管理。