Monday, June 30, 2025 6/30/2025

Improvement of Organ Function after Severe Hypovolemia

Award Number: R01HL076179
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2004
PERIOD OF PERFORMANCE END DATE: 12/31/2026

Group Awards By:

View Award Description

Improvement of Organ Function after Severe Hypovolemia - PROJECT DESCRIPTION: Hemorrhagic shock (HS) is a significant cause of death in the US and is frequently followed by infection and sepsis. As a result, many patients suffering from HS or HS+sepsis develop acute lung injury (ALI), a life-threatening complication. We have previously discovered that eCIRP, a new DAMP, released after HS or sepsis worsens disease severity and lethality. Our preliminary studies have confirmed elevated levels of eCIRP in the circulation of patients and animals after HS, as well as in the supernatant of macrophages exposed to hypoxia/reoxygenation (H/R). We have also shown that H/R or endotoxin promotes gasdermin D (GSDMD) cleavage into pore-forming subunits. The release of eCIRP after endotoxin was decreased by a GSDMD pore formation inhibitor and in cells from GSDMD knockout mice, implicating an important role of GSDMD in eCIRP’s active release. We have demonstrated that eCIRP activates stimulator of interferon genes (STING) in vitro and in vivo, leading to the upregulation and release of type I interferons (IFNs). Furthermore, we have shown that STING activation is critical to the development of systemic inflammation, tissue injury, ALI, and mortality after HS. We have also demonstrated that eCIRP promotes mitochondrial (mt) DNA fragmentation, thus providing a plausible mechanism for how eCIRP activates STING. In addition, we have shown for the first time that type I IFNs play a pivotal role in the development of ALI after HS. Based on these novel findings, we hypothesize that eCIRP, released through GSDMD pores, activates STING via fragmented mtDNA and increases the release of type I IFNs, ultimately leading to ALI and death after HS or HS+sepsis. Moreover, we have predicted in silico and confirmed in vitro that our newly discovered RNA mimic A12 binds to eCIRP with high affinity, in- hibiting eCIRP’s ability to induce TNFα release from macrophages. A12 had a long half-life in the circulation and reduced inflammation and tissue injury after HS. Therefore, we further hypothesize that eCIRP inhibition with A12 attenuates ALI and mortality in mice subjected to HS or HS+sepsis. In this project, we plan to establish the role of GSDMD pore formation on the active release of eCIRP, determine the detailed mechanism by which eCIRP activates STING, and examine the beneficial effects of the novel eCIRP inhibitor A12 on ALI and survival after HS or HS+sepsis. These studies shall provide novel mechanistic insights into the pathogenesis of ALI and organ injury after HS or HS complicated by sepsis, as well as a new potential therapeutic strategy to treat patients under those conditions.


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 = $487,376 )
2025	2025	THE FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Cardiovascular Diseases Research	000	16	12/19/2024	NON-COMPETING CONTINUATION	$487,376
														Subtotal = $487,376

Issue Date FY: 2024 ( Subtotal = $530,699 )
2024	2024	THE FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Cardiovascular Diseases Research	001	15	6/12/2024	NON-COMPETING CONTINUATION	$43,323
2024	2024	FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH, THE	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Cardiovascular Diseases Research	000	15	12/20/2023	NON-COMPETING CONTINUATION	$487,376
														Subtotal = $530,699

Issue Date FY: 2023 ( Subtotal = $541,529 )
2023	2023	FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH, THE	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Cardiovascular Diseases Research	001	14	3/10/2023	NON-COMPETING CONTINUATION	$54,153
2023	2023	FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH, THE	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Cardiovascular Diseases Research	000	14	1/3/2023	NON-COMPETING CONTINUATION	$487,376
														Subtotal = $541,529

Issue Date FY: 2022 ( Subtotal = $541,529 )
2022	2022	FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH, THE	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Cardiovascular Diseases Research	001	13	12/27/2021	COMPETING CONTINUATION	$541,529
2022	2019	FEINSTEIN INSTITUTES FOR MEDICAL RESEARCH, THE	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Cardiovascular Diseases Research	000	12	11/9/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $541,529

Issue Date FY: 2019 ( Subtotal = $425,101 )
2019	2019	FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH, THE	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Cardiovascular Diseases Research	000	12	5/10/2019	NON-COMPETING CONTINUATION	$425,101
														Subtotal = $425,101

Issue Date FY: 2018 ( Subtotal = $425,219 )
2018	2018	FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH, THE	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Cardiovascular Diseases Research	000	11	6/8/2018	NON-COMPETING CONTINUATION	$425,219
														Subtotal = $425,219

Issue Date FY: 2017 ( Subtotal = $424,817 )
2017	2017	FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH, THE	350 COMMUNITY DR	MANHASSET	NY	11030	NASSAU	USA	Cardiovascular Diseases Research	000	10	5/29/2017	NON-COMPETING CONTINUATION	$424,817
														Subtotal = $424,817

Issue Date FY: 2016 ( Subtotal = $441,963 )
2016	2016	FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH	350 COMMUNITY DRIVE	MANHASSET	NY	11030	NASSAU	USA	Cardiovascular Diseases Research	000	9	2/14/2016	COMPETING CONTINUATION	$441,963
														Subtotal = $441,963

Issue Date FY: 2014 ( Subtotal = $406,700 )
2014	2014	FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH	350 COMMUNITY DRIVE	MANHASSET	NY	11030	NASSAU	USA	Cardiovascular Diseases Research	000	8	5/20/2014	NON-COMPETING CONTINUATION	$406,700
														Subtotal = $406,700

Issue Date FY: 2013 ( Subtotal = $395,080 )
2013	2013	FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH	350 COMMUNITY DRIVE	MANHASSET	NY	11030	NASSAU	USA	Cardiovascular Diseases Research	000	7	5/31/2013	NON-COMPETING CONTINUATION	$395,080
														Subtotal = $395,080

Issue Date FY: 2012 ( Subtotal = $415,000 )
2012	2012	FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH	350 COMMUNITY DRIVE	MANHASSET	NY	11030	NASSAU	USA	Cardiovascular Diseases Research	000	6	5/23/2012	NON-COMPETING CONTINUATION	$415,000
														Subtotal = $415,000

Issue Date FY: 2011 ( Subtotal = $415,000 )
2011	2011	FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH	350 COMMUNITY DRIVE	MANHASSET	NY	11030	NASSAU	USA	Cardiovascular Diseases Research	000	5	8/12/2011	COMPETING CONTINUATION	$415,000
														Subtotal = $415,000

Issue Date FY: 2009 ( Subtotal = $0 )
2009	2007	NORTH SHORE-LONG ISLAND JEWISH RESEARCH INSTITUTE	350 COMMUNITY DRIVE	MANHASSET	NY	11030	NASSAU	USA	Cardiovascular Diseases Research	000	4	12/22/2008	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2007 ( Subtotal = $381,168 )
2007	2007	NORTH SHORE-LONG ISLAND JEWISH RESEARCH INSTITUTE	350 COMMUNITY DRIVE	MANHASSET	NY	11030	NASSAU	USA	Cardiovascular Diseases Research	000	4	1/25/2007	NON-COMPETING CONTINUATION	$381,168
														Subtotal = $381,168

Issue Date FY: 2006 ( Subtotal = $392,553 )
2006	2006	NORTH SHORE-LONG ISLAND JEWISH RESEARCH INSTITUTE	350 COMMUNITY DRIVE	MANHASSET	NY	11030	NASSAU	USA	Cardiovascular Diseases Research	000	3	2/13/2006	NON-COMPETING CONTINUATION	$392,553
														Subtotal = $392,553

Issue Date FY: 2005 ( Subtotal = $402,000 )
2005	2005	NORTH SHORE-LONG ISLAND JEWISH RESEARCH INSTITUTE	350 COMMUNITY DRIVE	MANHASSET	NY	11030	NASSAU	USA	Cardiovascular Diseases Research	000	2	12/24/2004	NON-COMPETING CONTINUATION	$402,000
														Subtotal = $402,000

Issue Date FY: 2004 ( Subtotal = $402,000 )
2004	2004	NORTH SHORE-LONG ISLAND JEWISH RESEARCH INSTITUTE	350 COMMUNITY DRIVE	MANHASSET	NY	11030	NASSAU	USA	Cardiovascular Diseases Research	000	1	1/15/2004	NEW	$402,000
														Subtotal = $402,000

Grand Total All Awards = $7,027,734

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Improvement of Organ Function after Severe Hypovolemia

Award Number: R01HL076179

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2004

PERIOD OF PERFORMANCE END DATE: 12/31/2026

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer