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Role of miRNA-TLR7 signaling in platelet activation and dysfunction in sepsis

Award Number: K08HL153784
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/01/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Role of miRNA-TLR7 signaling in platelet activation and dysfunction in sepsis - Project Summary Sepsis is a critical clinical condition that is caused by dysregulated host immune response to infection and characterized by organ failure and high mortality. Sepsis is associated with marked inflammation and hemostatic activation that often leads to widespread microvascular thrombus formation and global clotting dysfunction, a complication termed sepsis-induced coagulopathy (SIC). Toll-like receptors (TLRs) are innate immune receptors that respond to pathogen (PAMPs) or host-derived danger molecules (DAMPs) and drive profound inflammation. We have established a murine model of SIC characterized by time-dependent thrombocytopenia, procoagulant consumption, and global clotting dysfunction, and identified a critical role for TLR7 (a receptor for single-stranded RNAs, e.g., HIV RNA or microRNA) in the pathogenesis of SIC including thrombocytopenia, procoagulant (e.g., tissue factor, TF) production, and global clotting dysfunction. Moreover, we have observed increased circulating plasma miRNAs (e.g., miR-146a-5p) and extracellular vesicles (EVs, miRNA carrier) in sepsis, and a close correlation between the plasma RNA levels and sepsis severity. Both miR-146a-5p and septic plasma EVs induce proinflammatory and procoagulant response via a TLR7-dependent manner. Based on these data and the literature, we hypothesize that miRNA→TLR7 signaling plays an important role in regulating platelet activity and contributes to platelet dysfunction in SIC. To test this hypothesis, we propose the following three Specific Aims. In Aim 1, we will test the function and mechanisms of miRNA-TLR7 signaling in platelet activation. In Aim 2, we will determine the effect of EVs loaded with miR-146a-5p and septic plasma EVs on platelet activation and function. In Aim 3, we will investigate the role of TLR7 signaling in platelet activation and dysfunction in SIC. Completion of the proposed studies will provide new insight into the role and mechanism of miRNA-TLR7 signaling in regulating platelet activity and dysfunction in SIC, and potentially offer a novel therapeutic target.


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 = $0 )
2025	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Blood Diseases and Resources Research	000	5	8/26/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $155,150 )
2024	2024	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Blood Diseases and Resources Research	000	5	5/21/2024	NON-COMPETING CONTINUATION	$155,150
														Subtotal = $155,150

Issue Date FY: 2023 ( Subtotal = $155,150 )
2023	2023	UNIVERSITY OF MARYLAND, BALTIMORE	220 ARCH ST OFC LEVEL2	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Blood Diseases and Resources Research	000	4	5/23/2023	NON-COMPETING CONTINUATION	$155,150
														Subtotal = $155,150

Issue Date FY: 2022 ( Subtotal = $155,150 )
2022	2022	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Blood Diseases and Resources Research	000	3	5/17/2022	NON-COMPETING CONTINUATION	$155,150
														Subtotal = $155,150

Issue Date FY: 2021 ( Subtotal = $155,150 )
2021	2021	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Blood Diseases and Resources Research	000	2	6/1/2021	NON-COMPETING CONTINUATION	$155,150
														Subtotal = $155,150

Issue Date FY: 2020 ( Subtotal = $161,793 )
2020	2020	UNIVERSITY OF MARYLAND	220 ARCH ST RM 02148	BALTIMORE	MD	21201	BALTIMORE CITY	USA	Blood Diseases and Resources Research	000	1	8/20/2020	NEW	$161,793
														Subtotal = $161,793

Grand Total All Awards = $782,393

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Role of miRNA-TLR7 signaling in platelet activation and dysfunction in sepsis

Award Number: K08HL153784

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/01/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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