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Hyperhomocysteinemia, S-adenosylhomocysteine Accumulation, and Epigenetics

Award Number: R01GM098772
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: 03/31/2016

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Hyperhomocysteinemia, S-adenosylhomocysteine Accumulation, and Epigenetics - DESCRIPTION (provided by applicant): Elevated levels of plasma total homocysteine (tHcy), termed hyperhomocysteinemia (HHcy), are associated prospectively with increased incidence and mortality of many human diseases including coronary heart disease, stroke, dementia, Alzheimer's disease, diabetes, osteoporosis, cancer, neural tube defects and steatosis of the liver. The number and variety of diseases associated with elevated tHcy suggests that it may affect very basic cellular functions. Homocysteine is an intermediary metabolite produced from the hydrolysis of S-adenosylhomocysteine (SAH), which is a by-product of methylation reactions involving the methyl-donor S-adenosylmethionine (SAM). Studies from our lab and others show that elevations in tHcy in plasma are associated with elevations of intracellular SAH in tissues. Since SAH is a potent inhibitor of methyl-transfer reactions, such as those involved in the regulation of gene expression, this could point to a possible mechanism linking elevated tHcy to diverse disease states. Therefore, the overall goal of this proposal is to test the hypothesis that severe HHcy causes elevations in tissue SAH that results in inhibition of chromatin methylation and alters cellular gene expression in vivo. The proposed experiments will utilize an inducible genetic and a nutritional mouse model that each induce severe HHcy by a different mechanism. There are three specific aims: (1) Determine if HHcy is associated with elevated tissue SAH levels and global hypomethylation of DNA and histones. (2) Determine how HHcy affects gene-specific transcript levels, DNA, and histone methylation. (3) Determine if overexpression of SAH hydrolase can reverse the hypomethylation and gene expression phenotypes. Achieving these aims will lead to understanding the mechanism by which elevated tHcy causes disease and will give us new insight into potential interventions that could delay or eliminate the onset of homocysteine related diseases.


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: 2017 ( Subtotal = $0 )
2017	2015	INSTITUTE FOR CANCER RESEARCH, THE	333 COTTMAN AVE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Biomedical Research and Research Training	000	4	8/15/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2015 ( Subtotal = $439,150 )
2015	2015	INSTITUTE FOR CANCER RESEARCH	333 Cottman Ave	Philadelphia	PA	19111	PHILADELPHIA	USA	Biomedical Research and Research Training	001	4	6/26/2015	SUPPLEMENT FOR EXPANSION	$100,000
2015	2015	INSTITUTE FOR CANCER RESEARCH	333 Cottman Ave	Philadelphia	PA	19111	PHILADELPHIA	USA	Biomedical Research and Research Training	000	4	3/30/2015	NON-COMPETING CONTINUATION	$339,150
														Subtotal = $439,150

Issue Date FY: 2014 ( Subtotal = $339,150 )
2014	2014	INSTITUTE FOR CANCER RESEARCH	333 Cottman Ave	Philadelphia	PA	19111	PHILADELPHIA	USA	Biomedical Research and Research Training	000	3	3/20/2014	NON-COMPETING CONTINUATION	$339,150
														Subtotal = $339,150

Issue Date FY: 2013 ( Subtotal = $327,280 )
2013	2013	INSTITUTE FOR CANCER RESEARCH	333 Cottman Ave	Philadelphia	PA	19111	PHILADELPHIA	USA	Biomedical Research and Research Training	001	2	7/11/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$22,045
2013	2013	INSTITUTE FOR CANCER RESEARCH	333 Cottman Ave	Philadelphia	PA	19111	PHILADELPHIA	USA	Biomedical Research and Research Training	000	2	3/20/2013	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$305,235
														Subtotal = $327,280

Issue Date FY: 2012 ( Subtotal = $338,676 )
2012	2012	FOX CHASE CANCER CENTER	7701 BURHOLME AVENUE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Biomedical Research and Research Training	000	1	4/6/2012	NEW	$338,676
														Subtotal = $338,676

Grand Total All Awards = $1,444,256

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Hyperhomocysteinemia, S-adenosylhomocysteine Accumulation, and Epigenetics

Award Number: R01GM098772

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: 03/31/2016

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