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Alveolar epithelial carbohydrate metabolism in acute lung injury

Award Number: K08HL130586
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 01/01/2018
PERIOD OF PERFORMANCE END DATE: 03/15/2023

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Alveolar epithelial carbohydrate metabolism in acute lung injury - Acute lung injury (ALI) is an inflammatory lung disease characterized by its acute onset, severe hypoxia and pulmonary edema; which manifests itself in patients as acute respiratory distress syndrome (ARDS). At present, specific therapeutic approaches for ARDS are essentially unknown. Alveolar epithelial cells line the alveolar surface and type II alveolar epithelial cells (AT II) are known for their susceptibility to injurious insults that can lead to ALI. Inflammatory and immune responses in ALI are associated with dramatic shifts in tissue metabolism, which can either injurious or protective. A key protective mechanism involves enhanced pulmonary glycolysis, mediated through stabilization of the transcription factor hypoxia-inducible factor (HIF); however, how specific metabolic processes, notably those involving specific enzymatic glycolytic steps (and increase or decreases in intermediate substrates) affect the response of AT II cells during injury onset are largely unknown. We have developed a novel concept that in response to acute lung injury phosphofructokinase-2/fructose-2,6-bisphosphatase (PFKFB3 ) and its transcriptional regulator HIF1A are mediating anti-inflammatory activities of AT II cells. We hypothesize that excessive inflammation and cell injury in ALI are dampened by increases in intracellular lactate and pyruvate, which are induced by HIF1A-driven glycolysis and activation of PFKFB3 in alveolar type II cells. Harnessing those innate protective pathways could provide the base for novel therapeutic targets for ALI. In this resubmission we will: 1. Determine whether HIF1A is required for PFKFB3 activation in AT II cells (Specific Aim 1); 2. Determine whether the activation of PFKFB3 in AT II cells dampens inflammation due to ALI. We will uncover downstream effects of PFKFB3 activation, specifically the augmentation of glycolytic flux, and whether the glycolytic end products lactate/pyruvate quench excessive inflammation in AT II cells (Specific Aims 2a); 3. We will target alveolar- epithelial PFKFB3 therapeutically during ALI as we hypothesize, that activation of PFKFB3 will enhance the glycolytic flux and attenuate inflammation due to a dominant anti-inflammatory effect in AT II cells (Specific Aim 2b). To discern the role of the alveolar epithelium we utilize primary alveolar type II cells and tissue specific know out animals. Ventilator induced lung injury and acid aspiration will be used as murine models of ALI. To model lung injury ex vivo we will utilize an in vitro cyclic stretch system. Pharmacologic and genetic approaches will be utilized to study the functional role of HIF1A and PFKFB3 in vitro or ALI in vivo. We will target the AT II cells ex vivo and provide mechanistic data based on enhanced delivery of the glycolysis activator 2-6 fructose bisphosphate encapsulated by nanoparticles. We will characterize the epithelial glycolytic flux (metabolites, PFKFB3 and LDH activity, NADH/NAD measurement) and inflammatory response.


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: 2024 ( Subtotal = $0 )
2024	2022	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Lung Diseases Research	000	5	12/7/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $34,424 )
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Lung Diseases Research	000	5	12/28/2021	NON-COMPETING CONTINUATION	$34,424
														Subtotal = $34,424

Issue Date FY: 2021 ( Subtotal = $165,240 )
2021	2021	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Lung Diseases Research	000	4	12/18/2020	NON-COMPETING CONTINUATION	$165,240
														Subtotal = $165,240

Issue Date FY: 2020 ( Subtotal = $165,240 )
2020	2020	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Lung Diseases Research	000	3	1/4/2020	NON-COMPETING CONTINUATION	$165,240
														Subtotal = $165,240

Issue Date FY: 2019 ( Subtotal = $165,240 )
2019	2019	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Lung Diseases Research	000	2	1/19/2019	NON-COMPETING CONTINUATION	$165,240
														Subtotal = $165,240

Issue Date FY: 2018 ( Subtotal = $165,240 )
2018	2018	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Lung Diseases Research	000	1	1/1/2018	NEW	$165,240
														Subtotal = $165,240

Grand Total All Awards = $695,384

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Alveolar epithelial carbohydrate metabolism in acute lung injury

Award Number: K08HL130586

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 01/01/2018

PERIOD OF PERFORMANCE END DATE: 03/15/2023

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