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Genetic Analysis of Neuronal Hypoxia Resistance

Award Number: R01GM101972
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: 04/15/2012
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Genetic Analysis of Neuronal Hypoxia Resistance - PROJECT SUMMARY Hypoxia (O2 deprivation) plays a central role in diverse human diseases, including ischemic stroke, myocardial infarction, pulmonary hypertension, Cerebral Palsy, COVID-19, and cancer. Metazoans respond to hypoxia by employing the conserved hypoxia response pathway. The pathway senses O2 through a prolyl hydroxylase (PHD) enzyme, which uses O2 to hydroxylate specific proline side chains on the Hypoxia Inducible Factor α (HIFα). Once hydroxylated, HIFα is ubiquitinated by the Von Hippel-Lindau (VHL) ubiquitin ligase, resulting in its proteolysis. When O2 is abundant, HIFα is unstable. When hypoxia ensues, PHD enzymes lack O2 to hydroxylate HIFα, resulting in HIFα stabilization and the transcriptional regulation of multiple target genes that help the organism survive. Under some circumstances (e.g., solid tumors, stem cell niches), HIFα is activated despite adequate O2 levels (i.e., the Warburg effect), but how the response differs under aerobic conditions is unclear. While the HIFα pathway has been well studied in tissue culture, a full understanding of how it operates in specific tissues (particularly neurons) in vivo to provide tailored responses is needed. This proposal takes advantage of genetics and an intact, isogenic model organism (C. elegans) that can thrive under hypoxia, and whose environment and genetics can be controlled with fidelity and reproducibility. C. elegans possess single genes for the PHD (EGL-9), the VHL (VHL-1), and the HIFα (HIF-1). The overall premise of this proposal is that the hypoxia response pathway pathway protects against hypoxic damage by (1) removing mitochondria through mitophagy, which eliminates a source of ROS, and by (2) mobilizing antioxidant metabolism, which detoxifies ROS during hypoxia and reoxygenation. A better understanding of the pathway response will provide therapeutic targets for diseases associated with hypoxia. Preliminary ChIP-seq, RNA-seq, and metabolomics suggest that HIF-1 promotes gluconeogenesis, the pentose phosphate pathway, and antioxidant generation. We hypothesize that HIF-1 promotes this metabolic reprograming by binding an enhancer sequence and activating the expression of the PEP carboxykinase pck- 1, a key enzyme for moving metabolites through gluconeogenesis. Aim 1 tests this hypothesis by using CRISPR/Cas9 editing to remove this enhancer, then testing for the effects on HIF-1 binding, pck-1 and global gene expression, metabolism, oxidative stress resistance, neurodegeneration, and hypoxia survival. Preliminary cell biological approaches with a genetically encoded fluorescent reporter for mitophagy suggest that HIF-1 promotes mitophagy. We hypothesize that HIF-1 promotes mitophagy by binding enhancer sequences and activating the expression of the mitophagy receptors fndc-1 and dct-1. Aim 2 tests this hypothesis by using CRISPR/Cas9 editing to remove these enhancers, then testing for the effects on HIF- 1 binding, global gene expression, mitophagy and bulk autophagy, metabolism, oxidative stress resistance, neurodegeneration, and hypoxia survival.


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 = $337,267 )
2024	2024	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	000	12	7/17/2024	NON-COMPETING CONTINUATION	$337,267
														Subtotal = $337,267

Issue Date FY: 2023 ( Subtotal = $441,638 )
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	000	10	6/12/2023	SUPPLEMENT FOR EXPANSION	$104,371
2023	2023	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	001	11	7/7/2023	NON-COMPETING CONTINUATION	$337,267
														Subtotal = $441,638

Issue Date FY: 2022 ( Subtotal = $337,267 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	001	10	8/12/2022	NON-COMPETING CONTINUATION	$337,267
2022	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	000	8	12/7/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $337,267

Issue Date FY: 2021 ( Subtotal = $412,027 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	001	9	8/3/2021	COMPETING CONTINUATION	$412,027
2021	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	000	8	7/26/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $412,027

Issue Date FY: 2020 ( Subtotal = $325,501 )
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	000	8	7/30/2020	NON-COMPETING CONTINUATION	$325,501
														Subtotal = $325,501

Issue Date FY: 2019 ( Subtotal = $322,396 )
2019	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	000	7	7/16/2019	NON-COMPETING CONTINUATION	$322,396
														Subtotal = $322,396

Issue Date FY: 2018 ( Subtotal = $322,360 )
2018	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	002	6	7/31/2018	NON-COMPETING CONTINUATION	$322,360
2018	2017	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	001	5	5/14/2018	COMPETING CONTINUATION	$13
2018	2015	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	000	4	5/14/2018	NON-COMPETING CONTINUATION	-$13
														Subtotal = $322,360

Issue Date FY: 2017 ( Subtotal = $370,048 )
2017	2017	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	000	5	9/11/2017	COMPETING CONTINUATION	$370,048
														Subtotal = $370,048

Issue Date FY: 2015 ( Subtotal = $305,796 )
2015	2015	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLAZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	000	4	4/1/2015	NON-COMPETING CONTINUATION	$305,796
														Subtotal = $305,796

Issue Date FY: 2014 ( Subtotal = $356,128 )
2014	2014	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLAZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	000	3	3/24/2014	NON-COMPETING CONTINUATION	$356,128
														Subtotal = $356,128

Issue Date FY: 2013 ( Subtotal = $324,267 )
2013	2013	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLAZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	000	2	3/4/2013	NON-COMPETING CONTINUATION	$256,523
2013	2013	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLAZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	002	2	7/2/2013	NON-COMPETING CONTINUATION	$18,527
2013	2013	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLAZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	001	2	7/1/2013	SUPPLEMENT FOR EXPANSION	$49,217
														Subtotal = $324,267

Issue Date FY: 2012 ( Subtotal = $282,976 )
2012	2012	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLAZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Biomedical Research and Research Training	000	1	4/9/2012	NEW	$282,976
														Subtotal = $282,976

Grand Total All Awards = $4,137,671

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Genetic Analysis of Neuronal Hypoxia Resistance

Award Number: R01GM101972

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: 04/15/2012

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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