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

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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.