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NET stabilization: mechanistic and therapeutic studies studying the role of NETs in thromboinflammatory disease

Award Number: R00HL177830
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/17/2025
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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NET stabilization: mechanistic and therapeutic studies studying the role of NETs in thromboinflammatory disease - ABSTRACT In response to inflammatory stimuli, neutrophils (PMN) release neutrophil extracellular traps (NETs), webs of negatively-charged cell-free (cf) DNA complexed with positively-charged histones, which capture pathogens. However, the release of NETs (NETosis) can inflict tissue damage on the host and has been implicated in the severity of conditions like sepsis, linked with acute NETosis, and sickle cell disease (SCD), associated with chronic NETosis. While many advocate for treatments degrading NETs or inhibiting NETosis, these approaches may inadvertently release endothelial-damaging NET-degradation products (NDPs) or increase susceptibility to infection. An alternative strategy is NET stabilization—wherein NETs are preserved but modified to bolster microbial capture and diminish NDP release. This approach may be therapeutic in both sepsis and SCD. Platelet factor 4 (PF4) is a positively-charged chemokine released by activated platelets that binds to and cross- aggregates polyanions like heparin and DNA. PF4 similarly binds to NETs, causing them to become physically compact and resistant to nuclease digestion. PF4 also binds to negatively-charged molecules on the bacterial surface and markedly enhances their capture by NETs. An Fc-deglycosylated murine monoclonal antibody (moAb) targeting human PF4 complexed to polyanions enhances PF4's protective effects, improving survival in murine sepsis models. This proposal is designed to fill knowledge gaps in our understanding of the role of NETs in host defense to define when NETs should be preserved, providing justification for further exploration of NET- stabilizing therapeutics, such as PF4 and Fc-modified anti-PF4:polyanion antibodies. Specific Aim (SA) #1: Characterize the role of NETs in immune homeostasis. This aim is structured to clarify the role of NETs in host defense, exploring how impaired NETosis alters inflammatory cytokine levels, PMN gene expression, and gut microbiome composition in murine models. The impact of these changes on enteric bacterial pathogenicity and murine survival will be assessed using a polymicrobial sepsis model to clarify the role of NETs in host defense. SA#2:Define the mechanism by which PF4 and Fc-modified KKO limit bacterial dissemination. Studies in this aim will define the mechanisms by which PF4 and anti-PF4:polyanion antibodies enhance NET- mediated bacterial capture and determine whether these interventions promote bacterial killing. Comparative studies of KKO variants will be conducted in vitro and in murine infection models utilizing bacterial strains with variation in surface electrostatic charge. Murine studies will examine how different interventions affect the release of NDPs, bacterial dissemination, and microvascular damage. SA#3:Investigate the potential of NET-directed therapeutics in SCD. The final aim will investigate the use of NET-directed therapeutics in SCD, examining their potential to prevent endothelial cell injury and reduce bacterial infection risk. Patient plasma samples will be analyzed for NET levels, NDP concentrations, and endothelial cell damage markers, and therapeutic efficacy will be evaluated in an endothelial-lined microfluidic system.


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 = $445,000 )
2026	2026	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Blood Diseases and Resources Research	000	2	2/27/2026	NON-COMPETING CONTINUATION	$445,000
2026	2026	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Blood Diseases and Resources Research	001	2	6/12/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $445,000

Issue Date FY: 2025 ( Subtotal = $445,000 )
2025	2025	THE CHILDREN'S HOSPITAL OF PHILADELPHIA	3401 CIVIC CENTER BLVD	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Blood Diseases and Resources Research	000	1	3/17/2025	NEW	$445,000
														Subtotal = $445,000

Grand Total All Awards = $890,000

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NET stabilization: mechanistic and therapeutic studies studying the role of NETs in thromboinflammatory disease

Award Number: R00HL177830

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/17/2025

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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