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Hepatic ER stress contributes to morbidity and mortality after burn injury.

Award Number: R01GM087285
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2010
PERIOD OF PERFORMANCE END DATE: 08/31/2020

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Hepatic ER stress contributes to morbidity and mortality after burn injury. - DESCRIPTION (provided by applicant): Morbidity and mortality of severely burned patients still remain unacceptably high. Recent evidence indicates that hypermetabolism, a hallmark of severely burned patients, is a major contributor to these detrimental outcomes. Despite the widely recognized importance and complexity of the post-burn hypermetabolic response, the underlying mechanisms by which a thermal injury induces and sustains hypermetabolism for years after the injury are not well defined. Over the previous funding period, we identified that the endoplasmic reticulum (ER) stress response is profoundly affected by a severe burn. We further investigated the role of ER stress during the post-burn response and found that ER stress is associated with substantial metabolic alterations including insulin resistance (IR), lipolysis, cell death, inflammatory responses, and ultimately organ dysfunction. Our novel preliminary data indicate that augmenting ER stress greatly increases post-burn mortality. Thus, we hypothesize that the ER stress response is one of the central mediators of post-burn morbidity and mortality. As such, we aim to test the mechanistic basis by which the ER stress response is activated and leads to significantly greater morbidity. Specifically, the goal of this competitive renewal is to investigate the precise molecular mechanisms by which ER stress leads to increased morbidity and mortality. Based on extensive preliminary data we propose to determine the effects of augmented ER stress on mitochondrial function, calcium signaling via IP3R activity, and mTOR signaling at mitochondria-associated ER membranes (Aim 1). In Aim 2 we propose to test the novel hypothesis that unfolded proteins that accumulate during ER stress are Danger Associated Molecular Pattern (DAMP) molecules. Aim 3 will focus on our recent discovery that burn-induced ER stress causes profound activation of the hepatic NLRP3 inflammasome. We will test the hypothesis that released DAMPs, including ER stress-induced protein aggregates, can activate the NLRP3 inflammasome in the liver to stimulate IL-ß production and systemic inflammation contributing to post-burn multi-organ dysfunction. This project is highly innovative in that to-date the cellular and molecular mechanisms underlying the post-burn hypermetabolic response have not been identified and despite improved clinical care, the detrimental sequelae of this response leads to substantial morbidity and mortality after burn. The relevance of this project is that we will explore novel mechanisms that can lead to the development of new treatment avenues for burn patients or other patients in a hypermetabolic state.


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: 2022 ( Subtotal = $5 )
2022	2018	SUNNYBROOK RESEARCH INSTITUTE	2075 BAYVIEW AVE	TORONTO	ON			CAN	Biomedical Research and Research Training	000	8	9/26/2022	NON-COMPETING CONTINUATION	$5
														Subtotal = $5

Issue Date FY: 2021 ( Subtotal = -$5 )
2021	2018	SUNNYBROOK RESEARCH INSTITUTE	2075 BAYVIEW AVE	TORONTO	ON			CAN	Biomedical Research and Research Training	000	8	2/20/2021	NON-COMPETING CONTINUATION	-$5
														Subtotal = -$5

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2018	SUNNYBROOK RESEARCH INSTITUTE	2075 BAYVIEW AVE	TORONTO	ON	M4N 3M5		CAN	Biomedical Research and Research Training	000	8	1/28/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $274,513 )
2018	2018	SUNNYBROOK RESEARCH INSTITUTE	2075 BAYVIEW AVE	TORONTO	ON	M4N 3M5		CAN	Biomedical Research and Research Training	000	8	9/12/2018	NON-COMPETING CONTINUATION	$274,513
														Subtotal = $274,513

Issue Date FY: 2017 ( Subtotal = $274,513 )
2017	2017	SUNNYBROOK RESEARCH INSTITUTE	2075 BAYVIEW AVE	TORONTO	ON	M4N 3M5		CAN	Biomedical Research and Research Training	000	7	8/31/2017	NON-COMPETING CONTINUATION	$274,513
														Subtotal = $274,513

Issue Date FY: 2016 ( Subtotal = $274,513 )
2016	2016	SUNNYBROOK HEALTH SCIENCES CENTRE	2075 Bayview Avenue	TORONTO				CAN	Biomedical Research and Research Training	000	6	8/11/2016	NON-COMPETING CONTINUATION	$274,513
														Subtotal = $274,513

Issue Date FY: 2015 ( Subtotal = $272,948 )
2015	2015	SUNNYBROOK HEALTH SCIENCES CENTRE	2075 Bayview Avenue	TORONTO				CAN	Biomedical Research and Research Training	000	5	9/2/2015	COMPETING CONTINUATION	$272,948
														Subtotal = $272,948

Issue Date FY: 2013 ( Subtotal = $190,406 )
2013	2013	SUNNYBROOK HEALTH SCIENCES CENTRE	2075 Bayview Avenue	TORONTO				CAN	Biomedical Research and Research Training	000	4	8/16/2013	EXTENSION WITH OR WITHOUT FUNDS	$190,406
														Subtotal = $190,406

Issue Date FY: 2012 ( Subtotal = $199,247 )
2012	2012	SUNNYBROOK HEALTH SCIENCES CENTRE	2075 Bayview Avenue	TORONTO				CAN	Biomedical Research and Research Training	000	3	8/30/2012	NON-COMPETING CONTINUATION	$199,247
														Subtotal = $199,247

Issue Date FY: 2011 ( Subtotal = $201,900 )
2011	2011	SUNNYBROOK HEALTH SCIENCES CENTRE	2075 Bayview Avenue	TORONTO				CAN	Biomedical Research and Research Training	000	2	8/15/2011	NON-COMPETING CONTINUATION	$201,900
														Subtotal = $201,900

Issue Date FY: 2010 ( Subtotal = $210,600 )
2010	2010	SUNNYBROOK & WOMENS COLL HLTH SCIS CTR	2075 Bayview Avenue	TORONTO				CAN	Biomedical Research and Research Training	000	1	9/27/2010	NEW	$210,600
														Subtotal = $210,600

Grand Total All Awards = $1,898,640

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Hepatic ER stress contributes to morbidity and mortality after burn injury.

Award Number: R01GM087285

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/30/2010

PERIOD OF PERFORMANCE END DATE: 08/31/2020

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