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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

基本信息

批准号：
10454126
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
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10454126
关键词：
Abdomen Acute Affect 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 Persons 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 algorithm 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

项目摘要

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.

修改后的项目摘要/摘要败血症是一个广义术语，用于描述导致一个或多个器官系统功能障碍的感染。最近的数据表明，脓毒症不仅仅是一个单一的实体，而是一种至少有四种亚型（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，并且每种都具有独特的免疫特征。例如，Mars1 内型是迄今为止确定的四种内型中预后最差的。其典型特征是调节先天免疫和适应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。更好地识别异质脓毒症内型不仅可以解释为什么脓毒症临床试验迄今为止对结果没有产生统一的有益影响，而且还可能有助于开发实际用于医疗保健的诊断算法，从而满足紧迫的临床需求。我们假设抵抗素是严重脓毒症和脓毒性休克的一种新型生物标志物，可用于加强对患者不同脓毒症内型的分类。更具体地说，本提案要检验的假设是，腹部脓毒症发作后血液抵抗素水平升高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的不良后果。这一假设是由我们强有力的初步数据驱动的，这些数据表明抵抗素直接介导免疫功能障碍，并且在脓毒症后遗症最严重的患者中升高程度最高。我们的长期目标是（i）了解血液抵抗素浓度如何可能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）通过采用经过验证的、人性化的啮齿动物模型来确定人类抵抗素在腹部脓毒症急性期和恢复期中的作用，以及（2）结合临床数据确定血液抵抗素浓度的增量效用，以预测与不良结果相关的脓毒症亚型。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，以指导作为独立临床医生科学家的未来研究。申请人的导师团队涵盖了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：识别、表征和验证脓毒症特异性生物标志物，以推进内分型策略以及诊断和新疗法的未来评估。拟议的研究方案、教学工作和指导计划将使候选人能够转变为独立资助的医师科学家，重点关注脓毒症内型研究，这可能会改变致命疾病的临床管理。