This $181,772 project grant from the National Heart, Lung and Blood Institute will support research into coagulopathy in sepsis patients. The grantee, Beth Israel Deaconess Medical Center, will conduct an ancillary study using viscoelastic monitoring to examine the effects of randomly assigned fluid resuscitation strategies on coagulation parameters in sepsis patients. Specifically, the study aims to: 1) analyze how liberal versus restrictive fluid administration impacts coagulation measurements...
This Project Grant award from the National Heart, Lung, and Blood Institute (CFDA 93.837 Cardiovascular Diseases Research) provides $373,500 to the University of Southern California to conduct secondary analysis of existing datasets to define the neutrophil transcriptomic response to parenchymal damage. The key objectives are to: Define a gene expression signature common to neutrophils responding to septic shock with intraparenchymal source, multiple organ failure after major surgery, and...
This Project Grant award from the National Heart, Lung, and Blood Institute (CFDA 93.837 Cardiovascular Diseases Research) provides $1,398,770 to The University of Kentucky Research Foundation to investigate the role of serum amyloid A (SAA) and its association with high-density lipoprotein (HDL) in regulating sepsis-induced lung injury and mortality. The key goals are to: 1) determine how SAA mediates the resolution of sepsis by impeding neutrophil accumulation in injured lungs, and 2)...
This $294,244 Project Grant award, funded by the Department of Health and Human Services (DHHS) Agency for Healthcare Research and Quality (AHRQ) under the Research on Healthcare Costs, Quality and Outcomes (CFDA 93.226) program, supports research to identify sepsis phenotypes associated with antibiotic-resistant pathogens. The project aims to leverage machine learning techniques, including large language models applied to clinical notes, to augment electronic health record (EHR) data and define...
This federal Project Grant award from the National Heart, Lung, and Blood Institute (CFDA 93.837 Cardiovascular Diseases Research) provides $286,740 to the University of Nebraska Medical Center to conduct research on the mechanisms of complement activation in traumatic injury. The overarching goal is to elucidate how plasmin generation and endothelial glycocalyx shedding after trauma activate the complement system, and how this relates to organ failure in trauma patients. The 5-year research...
This Project Grant award of $462,000.00 from the National Institute of Allergy and Infectious Diseases (CFDA 93.855 - Allergy and Infectious Diseases Research) supports research to investigate how the human microbiome influences the immune response and survival outcomes in sepsis. The key objectives are to: Elucidate the underlying mechanisms by which the microbiome primes and regulates neutrophil function in healthy individuals. Determine the effects of microbiome-mediated neutrophil priming on...
The National Institutes of Health (NIH) National Institute of General Medical Sciences (NIGMS) awarded a $457,498 Project Grant to Texas A&M University to conduct research on a targeted nutritional approach to restore muscle health and physical activity in patients recovering from sepsis. The 4-year grant (9/1/2024 - 8/31/2028) aims to test the hypothesis that a combined nutritional formulation of beta-hydroxy beta-methylbutyric acid (HMB) and essential amino acids (EAA) is superior to EAA...
This $186,221 Project Grant award from the National Institute of Allergy and Infectious Diseases (CFDA 93.855 - Allergy and Infectious Diseases Research) supports research to develop personalized sepsis therapies for pediatric patients. The key objectives are to: Augment sepsis phenotypes by incorporating high-frequency physiological data to identify additional subtypes and predict disease progression. Retrospectively develop and externally validate predictive algorithms to identify...
This $598,228 Project Grant award from the National Heart, Lung, and Blood Institute (CFDA 93.837 Cardiovascular Diseases Research) aims to investigate the role of endoplasmic reticulum autophagy (ER-phagy) in the immune response during sepsis. The research team at the University of Illinois will use state-of-the-art methods to define the mechanisms by which ER-phagy regulates the NLRP3 inflammasome activation and cytokine release in macrophages, ultimately contributing to lung injury during...
This Project Grant award from the National Heart, Lung, and Blood Institute (CFDA 93.837 Cardiovascular Diseases Research) provides $344,304 to Trustees of Boston University to conduct a study titled "A Learning Health System Approach to Improve the Effectiveness of Blood Transfusions During Septic Shock." The project aims to investigate the effectiveness of blood transfusion strategies for patients with septic shock, a common and often fatal condition characterized by acute...
MECHANISM OF TRAUMA/HEMORRHAGIC SHOCK-PREDISPOSED SEPSIS - ABSTRACT IT IS WELL KNOWN IN CLINICS THAT SURVIVORS OF SEVERE TRAUMA AND HEMORRHAGIC SHOCK (T/HS) FACE A SIGNIFICANT RISK OF DEVELOPING SEPSIS FROM INFECTIONS, WHICH CAUSES HIGH MORTALITY. HOWEVER, AS THE MECHANISMS OF T/HS- PREDISPOSED INFECTION REMAIN UNCLEAR, FEW SPECIFIC TARGETS LINKING T/HS TO ELEVATED RISK OF SEPSIS HAVE BEEN IDENTIFIED. THIS PROPOSAL AIMS TO ADDRESS THIS IMPORTANT CLINICAL PROBLEM BY ELUCIDATING A PREVIOUSLY UNKNOWN MECHANISM OF T/HS REGULATION OF IMMUNOMETABOLISM THAT PREDISPOSES PATIENTS TO INFECTION. HERE, WE FOCUS ON THE FORMATION OF A POSITIVE FEEDBACK LOOP FOR 12(S)-HETE-ALOX15, WHICH IS AN UNUSUAL MECHANISM FOR THE METABOLITE,12(S)-HETE, TO UPREGULATE THE EXPRESSION OF ITS RATE-LIMITING ENZYME ALOX15. EMERGING STUDIES HAVE DEMONSTRATED THE IMPORTANT ROLE OF FATTY ACIDS (FAS) IN THE REGULATION OF INFLAMMATION. A PREVIOUS STUDY IDENTIFIED PLASMA 12(S)-HYDROXYEICOSATETRAENOIC ACID [12(S)-HETE] AS A BIOMARKER PREDICTING TRAUMA PATIENT MORTALITY, WHERE 12(S)-HETE LEVELS IN NON-SURVIVING PATIENTS WITH SEVERE TRAUMA ARE 5-TIME HIGHER THAN THOSE IN TRAUMA SURVIVORS AT THE TIME OF HOSPITAL ADMISSION. 12(S)-HETE IS A METABOLITE FROM ARACHIDONIC ACID (AA) GENERATED BY LIPOXYGENASES. ALOX15, A LIPOXYGENASE, IS THE RATE- LIMITING ENZYME IN GENERATING 12(S)-HETE. IN OUR PRELIMINARY STUDIES, WE OBSERVED THAT 1) 12(S)-HETE INCREASED HOST SUSCEPTIBILITY TO INFECTION FOLLOWING T/HS; 2) 12(S)-HETE INDUCES ENHANCED ALOX15 EXPRESSION IN MACROPHAGES (MPS), WHICH FORMS A POSITIVE FEEDBACK LOOP THAT LEADS TO ENHANCED GENERATION OF 12(S)-HETE, AUGMENTED MP DEATH, AND DECREASED BACTERIA CLEARANCE; AND 3) BLOCKING THE FEEDBACK LOOP BY GENETIC DELETION OF 12(S)-HETE RECEPTOR GPR31 OR SUPPRESSION OF ALOX15 INCREASED THE BACTERIA CLEARANCE ABILITY IN THE LUNGS AND IMPROVED THE SURVIVAL RATE FOLLOWING POST-T/HS INFECTION. BASED ON THESE FINDINGS, WE HYPOTHESIZE THAT THE 12(S)-HETE-INDUCED ALOX15 EXPRESSION FORMS A POSITIVE FEEDBACK LOOP AND SERVES AS A NOVEL MECHANISM UNDERLYING T/HS-PREDISPOSED SEPSIS. BLOCKING THE FEEDBACK LOOP BY ALOX15 INHIBITOR MAY PRESENT A THERAPEUTIC AND PREVENTIVE STRATEGY FOR T/HS-PREDISPOSED SEPSIS. WE PROPOSE TWO SPECIFIC AIMS TO TEST THIS HYPOTHESIS: AIM 1 IS TO DETERMINE THE MECHANISM OF 12(S)- HETE UPREGULATION OF ALOX15 EXPRESSION IN T/HS; AND AIM 2 IS TO DETERMINE THE ROLE OF 12(S)-HETE- ALOX15 FEEDBACK LOOP IN THE MECHANISM OF T/HS-PREDISPOSED SEPSIS. TO OUR KNOWLEDGE, THIS STUDY IS THE FIRST ATTEMPT TO EVALUATE THE ROLE OF THE T/HS-INDUCED 12(S)-HETE- ALOX15 FEEDBACK LOOP IN INFECTION AND SEPSIS SUSCEPTIBILITY. WE REASON THAT THE METABOLITE-ENZYME FEEDBACK LOOP MAY REPRESENT AN UNEXPLORED MECHANISM OF T/HS-PRIMED INFECTION. UNDERSTANDING THIS MECHANISM MAY PROVIDE A NOVEL THERAPEUTIC TARGET FOR THE PREVENTION AND TREATMENT OF POST-T/HS SEPSIS.