Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

NETs: Protection or Harm in Neonatal Inflammation and Infection

Award Number: R01HD093826
ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/20/2018
PERIOD OF PERFORMANCE END DATE: 02/28/2029

Group Awards By:

View Award Description

NETs: Protection or Harm in Neonatal Inflammation and Infection - We have successfully used our novel Neutrophil Extracellular Trap (NET)-Inhibitory Peptides (NIPs) to show that in experimental models of neonatal sepsis NETs increase inflammatory injury and mortality. Neutrophils extrude NETs, extracellular lattices of decondensed chromatin decorated with histones and antimicrobial proteins, to protect against infection by trapping and killing microbes. NIPs, however, inhibit NETs, decrease inflammatory injury, and increase survival in models of experimental sepsis whether used alone or in combination with antimicrobial agents like meropenem. The receptor for NIPs and the cellular mediators of NIP-induced NET inhibition remain unknown. This project will determine whether proteinase 3 (PR3), a serine protease present on the outer membrane of a subset of unstimulated neutrophils, serves as that receptor and whether NIPs must bind PR3 to inhibit NET formation. Using NIPs as tools for discovery, we will evaluate PR3 as a novel endogenous regulatory checkpoint that limits NET-mediated inflammatory tissue damage in sepsis. PR3 represents a novel NIP binding partner which complexes CD177 and phospholipid scramblase 1 (PLSCR-1) on the neutrophil surface. CD177 activates the Mac-1 integrin on neutrophils leading to reactive oxygen species generation and NET formation. PLSCR-1 mediates neutrophil apoptosis and facilitates membrane flipping in neutrophil lipid rafts. Using surrogate neutrophils differentiated from human hematopoietic stem cells and CRISPR/cas9 gene editing, our preliminary data show that NIP-mediated NET inhibition in neutrophils requires PR3 but NET formation does not. Further, PR3 knockout mouse pups fail to respond to NIPs and show decreased survival compared to wild type NIP- treated pups, suggesting that NIPs require PR3 to inhibit NET formation in vivo. Additional data show that NIP binding to PR3 may alter CD177- and PLSCR-1-dependent effects on NET formation and neutrophil apoptosis. This proposal outlines three specific aims that will provide novel insights into PR3’s role as an anti-inflammatory mediator of NET inhibition by NIPs in neonatal sepsis. We will: 1) determine whether PR3 is a/the required receptor of NIPs; 2) determine whether the PR3-complexed proteins CD177 and PLSCR-1 facilitate PR3- dependent NIP-mediated NET inhibition and apoptosis, respectively; and 3) determine whether neutrophil PR3 expression protects or harms in neonatal sepsis. These studies will significantly advance the field by identifying the receptor for NIPs on neutrophils, determining the downstream mechanistic effects of NIP binding to PR3, and evaluating the importance of neutrophil PR3 expression in preclinical models of neonatal sepsis. Our laboratory is uniquely poised to answer these innovative, translational, and mechanistic questions regarding PR3 and NIPs in neonatal sepsis. As demonstrated during our initial award, the impact of these studies will extend beyond neonatal sepsis to other inflammatory syndromes of prematurely born infants and adults, e.g., necrotizing enterocolitis, ischemic stroke, and COVID-19.


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 = $507,761 )
2026	2026	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Child Health and Human Development Extramural Research	000	7	3/5/2026	NON-COMPETING CONTINUATION	$507,761
														Subtotal = $507,761

Issue Date FY: 2025 ( Subtotal = $501,139 )
2025	2025	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Child Health and Human Development Extramural Research	000	6	3/27/2025	COMPETING CONTINUATION	$501,139
														Subtotal = $501,139

Issue Date FY: 2024 ( Subtotal = -$1,987 )
2024	2022	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Child Health and Human Development Extramural Research	000	5	12/27/2023	NON-COMPETING CONTINUATION	-$1,987
														Subtotal = -$1,987

Issue Date FY: 2022 ( Subtotal = $321,317 )
2022	2022	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Child Health and Human Development Extramural Research	000	5	5/27/2022	NON-COMPETING CONTINUATION	$321,317
														Subtotal = $321,317

Issue Date FY: 2021 ( Subtotal = $321,317 )
2021	2021	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Child Health and Human Development Extramural Research	000	4	4/19/2021	NON-COMPETING CONTINUATION	$321,317
														Subtotal = $321,317

Issue Date FY: 2020 ( Subtotal = $327,875 )
2020	2020	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Child Health and Human Development Extramural Research	000	3	4/27/2020	NON-COMPETING CONTINUATION	$327,875
														Subtotal = $327,875

Issue Date FY: 2019 ( Subtotal = $327,875 )
2019	2019	UNIVERSITY OF UTAH, THE	201 S PRESIDENT CIRCLE RM 408	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Child Health and Human Development Extramural Research	000	2	4/25/2019	NON-COMPETING CONTINUATION	$327,875
														Subtotal = $327,875

Issue Date FY: 2018 ( Subtotal = $327,875 )
2018	2018	UNIVERSITY OF UTAH, THE	201 S PRESIDENT CIRCLE RM 408	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Child Health and Human Development Extramural Research	000	1	7/19/2018	NEW	$327,875
														Subtotal = $327,875

Grand Total All Awards = $2,633,172

Top

All Categories

About

Search

Reports

Data Submission

Award Information

NETs: Protection or Harm in Neonatal Inflammation and Infection

Award Number: R01HD093826

ORGANIZATION: NATIONAL INSTITUTE OF CHILD HEALTH AND HUMAN DEVELOPMENT

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/20/2018

PERIOD OF PERFORMANCE END DATE: 02/28/2029

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer