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Novel intrinsic endothelial stem cells responsible for lung endothelial regeneration and vascular repair in ARDS

Award Number: R01HL172447
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/22/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2027

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Novel intrinsic endothelial stem cells responsible for lung endothelial regeneration and vascular repair in ARDS - Acute respiratory distress syndrome (ARDS) is a complex, multi-factorial syndrome with an unacceptable high mortality rate. Endothelial injury characterized by persistently increased lung microvascular permeability resulting in protein-rich lung edema is a hallmark of ARDS. In both animal models of acute lung injury induced by sepsis and ARDS patients, there are mounting evidence demonstrate loss of endothelial cells (ECs). Recent studies provide some information that ECs play predominant role in lung endothelial regeneration. However, the pulmonary vascular ECs are quite heterogenous. It is unknown whether all resident ECs contribute to endothelial regeneration following sepsis-induced vascular injury. The most important question in the field is whether there is a special endothelial stem cells responsible for endothelial regeneration and vascular repair following sepsis-induced lung injury. Our supporting data show that there is a novel rare subpopulation of ECs responsible for lung endothelial regeneration and vascular repair following sepsis-induced lung injury. These cells express many of the genes essential for cell cycle progression and proliferation and also some of the stem cell genes, however, not the markers of recently identified vascular endothelial stem cells/progenitor cells such as Apelin, CD157 and EPCR. Based on their unique expression of 2 genes, we named this rare subpopulation of ECs as UC+ endothelial stem cells (UC+ESCs). Genetic depletion of UC+ESCs in mouse lungs led to inhibited endothelial regeneration and impaired vascular repair resulting in persistent inflammatory lung injury. Thus, we hypothesize that UC+ESCs are the long-sought endothelial stem cells responsible for endothelial regeneration and vascular repair following inflammatory lung injury induced by sepsis challenge. The proposed studies will address the following Specific Aims. Studies in AIM 1 will determine the fundamental role of UC+ESCs in vascular repair and resolution of inflammatory lung injury induced by sepsis challenge via genetic depletion of UC+ESCs. Two complementary sepsis models including i.p. LPS and cecal ligation and puncture (CLP) which induces polymicrobial sepsis will be used. AIM 2 will define the role of UC+ESCs in regenerating endothelial subpopulation(s) and the molecular mechanisms of UC+ESC proliferation and expansion following sepsis challenge. These studies will define a novel rare endothelial stem cell subpopulation responsible for endothelial regeneration following sepsis- induced inflammatory lung injury and provide a paradigm shift in our understanding of the cellular mechanisms of endothelial regeneration and vascular repair. We believe successful completion of the studies will lead to novel therapeutic strategy to harness this specific intrinsic endothelial stem cell subpopulation for the prevention and effective treatment of ARDS induced by sepsis.


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 = $721,176 )
2026	2026	ANN & ROBERT H LURIE CHILDRENS HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Lung Diseases Research	000	3	2/12/2026	NON-COMPETING CONTINUATION	$721,176
														Subtotal = $721,176

Issue Date FY: 2025 ( Subtotal = $759,133 )
2025	2025	ANN & ROBERT H LURIE CHILDRENS HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Lung Diseases Research	000	2	12/26/2024	NON-COMPETING CONTINUATION	$683,221
2025	2025	ANN & ROBERT H LURIE CHILDRENS HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Lung Diseases Research	001	2	8/27/2025	NON-COMPETING CONTINUATION	$75,912
														Subtotal = $759,133

Issue Date FY: 2024 ( Subtotal = $759,133 )
2024	2024	ANN & ROBERT H LURIE CHILDRENS HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Lung Diseases Research	001	1	7/17/2024	NEW	$75,912
2024	2024	ANN & ROBERT H LURIE CHILDRENS HOSPITAL OF CHICAGO	225 E CHICAGO AVE	CHICAGO	IL	60611	COOK	USA	Lung Diseases Research	000	1	12/22/2023	NEW	$683,221
														Subtotal = $759,133

Grand Total All Awards = $2,239,442

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Novel intrinsic endothelial stem cells responsible for lung endothelial regeneration and vascular repair in ARDS

Award Number: R01HL172447

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/22/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2027

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