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Mechanisms of cardiomyocyte dysfunction in pediatric septic shock

Award Number: K08GM148957
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 02/01/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Mechanisms of cardiomyocyte dysfunction in pediatric septic shock - PROJECT SUMMARY / ABSTRACT Title: Mechanisms of cardiomyocyte dysfunction in pediatric septic shock Despite decades of research in pediatric sepsis, mortality remains at approximately 25% for children with septic shock. Sepsis-associated myocardial dysfunction (SAMD) is common in children and has an association with mortality that is not simply a reflection of the severity of illness. As no disease-modifying therapies exist for SAMD, there is a critical need to understand the biologic basis of cardiomyocyte dysfunction in sepsis. Furthermore, there is a need for novel human modeling with patient-derived materials given the failure to translate molecular discoveries in murine models of sepsis to improvements in human organ injury. Our objectives are to establish human induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (hiPSC-CMs) as a model for cardiomyocyte dysfunction in pediatric sepsis and to examine the roles of host genetic background and serum factors in the pathogenesis of SAMD. We have built upon our large, established biobank of serum from children with sepsis to study the cardiomyocyte response to septic serum banked from children who did and who did not have SAMD. We have found that the contractility of hiPSC-CMs is depressed by serum banked from children with SAMD but not by control septic serum from children without SAMD. This depressant effect was reversible after removal of the serum, suggesting this was not reflective of cell death. Furthermore, we identified a significant association of interleukin-8 (IL-8) with SAMD in children with septic shock and found that recombinant human IL-8 depresses hiPSC-CM contractility. Our proposal will address three important questions as specific aims: First, we will determine whether hiPSC-CMs and cardiomyocytes derived from the same children share common functional and transcriptional patterns of responses when exposed to banked septic serum. We will provide a comprehensive comparison of hiPSC-CMs to ex vivo cardiomyocytes by isolating cardiomyocytes from discarded surgical tissue from children undergoing cardiac surgery and by generating hiPSC-CMs from these same patients. Second, we will determine the degree to which host genetic background contributes to cardiomyocyte dysfunction in SAMD. We will develop hiPSC- CMs from pediatric patients with and without SAMD to determine responses to septic serum to identify patterns of functional and transcriptional responses associated with susceptibility to SAMD. Third, we will dissect the role of IL-8 signaling in cardiomyocyte dysfunction in sepsis. We will employ a combination of IL-8 modulation in serum and IL-8 receptor (CXCR1 and CXCR2) knockouts in hiPSC-CMs, providing evidence for IL-8 blockade as a potential therapeutic target in SAMD. This career development proposal will build on my background in translational research in myocardial dysfunction to gain new expertise in cardiomyocyte functional analysis, hiPSC generation and differentiation, and next-generation RNA sequencing technology to facilitate my transition to independence as a physician-scientist focused on elucidating and targeting mechanisms of pediatric SAMD.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $192,024 )
2025	2025	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Biomedical Research and Research Training	000	3	1/24/2025	NON-COMPETING CONTINUATION	$192,024
														Subtotal = $192,024

Issue Date FY: 2024 ( Subtotal = $192,024 )
2024	2024	CHILDRENS HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Biomedical Research and Research Training	000	2	1/5/2024	NON-COMPETING CONTINUATION	$192,024
														Subtotal = $192,024

Issue Date FY: 2023 ( Subtotal = $192,024 )
2023	2023	CHILDREN'S HOSPITAL MEDICAL CENTER	3333 BURNET AVE	CINCINNATI	OH	45229	HAMILTON	USA	Biomedical Research and Research Training	000	1	1/18/2023	NEW	$192,024
														Subtotal = $192,024

Grand Total All Awards = $576,072

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Mechanisms of cardiomyocyte dysfunction in pediatric septic shock

Award Number: K08GM148957

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 02/01/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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