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Mechanisms and outcomes of the hyperglycemic shift to necroptosis in myeloid cells

Award Number: R15HL135675
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/15/2016
PERIOD OF PERFORMANCE END DATE: 07/31/2024

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Mechanisms and outcomes of the hyperglycemic shift to necroptosis in myeloid cells - PROJECT SUMMARY The two main pathways of programmed cell death (PCD) are apoptosis, which is non-inflammatory, and necroptosis, which is inflammatory. Neonatal hypoxia-ischemia (HI) brain injury has an incidence of 1 to 6 per 1000 full-term births and is the third most common cause of neonatal death. Damage in this injury is primarily driven by apoptosis. Hyperglycemia, which may be caused by glucose infusion, insulin resistance, diabetes mellitus, or stress due to injury in the neonate, exacerbates HI-brain injury. We have shown that hyperglycemia induces a shift from apoptosis to necroptosis in cultured monocytes and microglia. We have also shown that hyperglycemia exacerbates neonatal HI-brain injury in vivo in a manner that depends on necroptosis concurrent with increases in necroptosis kinases and decreases in markers of apoptosis. We hypothesize that hyperglycemia promotes a shift from apoptosis to necroptosis in neurons, microglia, and infiltrating monocytes during neonatal HI-brain injury. In this context, we believe that in the inflammatory milieu of the brain, microglia and monocytes will encounter cell death agonists and undergo necroptosis leading to death of bystander neurons exacerbating the injury. We will explore the underlying mechanism of the hyperglycemic shift to necroptosis in monocytes and microglia and determine if the shift to necroptosis in monocytes and microglia leads to death of bystander neurons thereby exacerbating neonatal HI-brain injury. In Aim 1A we will analyze the role of mitochondrial factors in the hyperglycemic shift to necroptosis and their relation to increases in ROS during this phenomenon. In Aim 1B, we will explore the trafficking of cell death factors to the nucleus during the hyperglycemic shift to necroptosis as well as effects on gene expression. In Aim 1C we will test the hypothesis that the hyperglycemic shift from apoptosis to necroptosis in monocytes and microglia leads to bystander death of cultured neurons. As part of this aim we will determine factors responsible for bystander neuronal death and mechanisms of bystander death. In Aim 2 we will determine the mechanism of the hyperglycemic shift from apoptosis to necroptosis during neonatal HI-brain injury in vivo. In Aim 2A we will analyze the role of microglia and monocytes in the hyperglycemic shift to necroptosis during neonatal HI-brain injury using MaFIA mice. In Aim 2B we will explore the role of bystander neuronal death in the injury via intracerebroventricular administration of myeloid vesicles. This work will reveal molecular targets for therapeutic intervention. We believe that, due to PCD shift in hyperglycemia, different therapeutic approaches will be necessary in the context of euglycemia vs. hyperglycemia.


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 = $0 )
2025	2021	ALBANY COLLEGE OF PHARMACY AND HEALTH SCIENCES	106 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Blood Diseases and Resources Research	000	2	12/16/2024	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2021	ALBANY COLLEGE OF PHARMACY AND HEALTH SCIENCES	106 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Blood Diseases and Resources Research	000	2	1/11/2024	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $480,000 )
2021	2021	ALBANY COLLEGE OF PHARMACY AND HEALTH SCIENCES	106 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Blood Diseases and Resources Research	000	2	1/25/2021	COMPETING CONTINUATION	$480,000
2021	2017	ALBANY COLLEGE OF PHARMACY AND HEALTH SCIENCES	106 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Blood Diseases and Resources Research	001	1	6/4/2021	NEW	$0
														Subtotal = $480,000

Issue Date FY: 2020 ( Subtotal = $0 )
2020	2017	ALBANY COLLEGE OF PHARMACY AND HEALTH SCIENCES	106 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Blood Diseases and Resources Research	000	1	12/17/2019	NEW	$0
														Subtotal = $0

Issue Date FY: 2017 ( Subtotal = $480,000 )
2017	2017	ALBANY COLLEGE OF PHARMACY AND HEALTH SCIENCES	106 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Blood Diseases and Resources Research	001	1	12/19/2016	NEW	$0
2017	2017	ALBANY COLLEGE OF PHARMACY AND HEALTH SCIENCES	106 NEW SCOTLAND AVE	ALBANY	NY	12208	ALBANY	USA	Blood Diseases and Resources Research	000	1	12/14/2016	NEW	$480,000
														Subtotal = $480,000

Grand Total All Awards = $960,000

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Mechanisms and outcomes of the hyperglycemic shift to necroptosis in myeloid cells

Award Number: R15HL135675

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/15/2016

PERIOD OF PERFORMANCE END DATE: 07/31/2024

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