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Deltex E3 ubiquitin ligase 3L: A novel mechanism and protective approach in sepsis

Award Number: R01HL187387
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/20/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2030

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Deltex E3 ubiquitin ligase 3L: A novel mechanism and protective approach in sepsis - Project summary: Sepsis is a life-threatening organ dysfunction and a leading cause of mortality and critical illness worldwide. The induction of a rapid insulin resistance and sepsis-induced cardiac dysfunction are almost universal findings in sepsis and key determinant factors for multi-organ dysfunction and a high mortality rate. The intervention to sepsis-induced cardiac depression and septic insulin resistance are a critical treatment strategy. However, the precise mechanism(s) for sepsis-induced insulin resistance and septic cardiac dysfunction are unclear, and the lack of mechanism-based therapeutics designed for two crucial events underscore a significant challenge. We recently found that Deltex E3 ubiquitin ligase 3L (DTX3L) shows a remarkable decline in muscle in sepsis. Muscle-targeted silencing of DTX3L enhances release of inflammatory cytokines in sepsis. This promotes us to answer whether DTX3L serves as a previously unknown target to mediate septic cardiac dysfunction and insulin resistance. The PI found that DTX3L formed an unique association with HDAC4 in cardiac muscle and induced an ubiquitination of HDAC4. Whether muscle DTX3L mediates ubiquitination of HDAC4 in the critical control of septic insulin resistance and cardiac dysfunction is an unknown question. With these exciting studies, we will test our central hypothesis that muscle-specific DTX3L leads to the ubiquitination and degradation of HDAC4, which is required to mitigate septic insulin resistance and cardiac dysfunction. Two specific aims as outlined below are designed to rigorously test this hypothesis-driven project and to validate the translational significance of muscle-specific DTX3L regulation of HDAC4 in overcoming septic insulin resistance and cardiac dysfunction. Specific Aim #1: By using CRISPR/Cas9 gene editing developed muscle-specific DTX3L knockout genetic mouse model, we will rigorously determine the key contribution of DTX3L to mediating insulin resistance and cardiac dysfunction in sepsis. We will further determine whether the loss of DTX3L-induced detrimental effect could be rescued by muscle-specific deletion of HDAC4 to unravel the function of DTX3L ubiquitination of HDAC4 as a novel working model in sepsis. Specific Aim #2: By developing mRNA integrated therapeutics, RNA interference technology, and tissue-targeting lipid nanoparticle (LNP) cutting-edge technologies, we will explore the efficacy of the novel therapeutic modality of muscle-targeted DTX3LmRNA for protein replacement and silencing of HDAC4. The proposed studies will for the first time define muscle-specific DTX3L constituting a novel pathway in sepsis to mediate sepsis-induced insulin resistance. Muscle-specific targeted LNP formation of DTX3L mRNA for protein replacement and silencing of HDAC4 will provide novel insights in its Significant Impact on treatment of sepsis, cardiovascular disease, metabolic disease and other diseases.


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: 2026 ( Subtotal = $712,858 )
2026	2026	RHODE ISLAND HOSPITAL	593 EDDY ST	PROVIDENCE	RI	02903	PROVIDENCE	USA	Cardiovascular Diseases Research	000	1	8/25/2026	NEW	$712,858
														Subtotal = $712,858

Grand Total All Awards = $712,858

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Deltex E3 ubiquitin ligase 3L: A novel mechanism and protective approach in sepsis

Award Number: R01HL187387

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/20/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2030

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