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OXIDATION HYPOTHESIS REVISITED: HAPTOGLOBIN GENOTYPE & DIABETIC ATHEROSCLEROSIS

Award Number: R01DK085226
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2009
PERIOD OF PERFORMANCE END DATE: 08/31/2014

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OXIDATION HYPOTHESIS REVISITED: HAPTOGLOBIN GENOTYPE & DIABETIC ATHEROSCLEROSIS - Project Abstract Acute ischemic syndromes due to a higher incidence of plaque rupture and thrombosis are common complications associated with Diabetes Mellitus (DM). The oxidative modification hypothesis of atherosclerosis predicts that oxidative events in the vessel wall are responsible for the initiation and progression of atherosclerotic lesions. As DM represents a state of heightened oxidative stress, the accelerated atherosclerosis and increased atherothrombosis in DM are thought to be due to increased oxidative modifications. Paradoxically, anti-oxidant strategies to reduce cardiovascular events from atherosclerosis in DM have failed, possibly due to the inadequate nature of patient selection. High dose antioxidant therapy may only provide benefit to individuals with particularly high levels of oxidative stress. We have shown, in vitro and in vivo, that the 2 allele of the Haptoglobin (Hp) gene is associated with high levels of oxidative stress in DM. In clinical studies we have found that DM individuals with the Hp 2-2 genotype have as much as a 500% increase in cardiovascular events as compared to Hp 1-1 DM individuals. Based on this association of the Hp genotype and oxidative stress we have suggested a pharmacogenomic approach for identifying individuals who will benefit from antioxidant therapy. We have recently prospectively tested this approach in a double-blind placebo controlled trial and found that antioxidant therapy with vitamin E significantly reduced atherothrombosis in Hp 2-2 DM individuals. We hypothesize that the Hp 2-2 genotype interacts with DM to promote HDL oxidative modification and dysfunction as a result of the direct association of the Hp 2-2-Hb complex with HDL. To test our hypothesis we have designed both mechanistic and interventional studies using a unique mouse model expressing the Hp 2 protein and human banked serum from ICARE and two prospective interventional studies.. The specific aims are to assess the relationship between the Hp genotype and HDL structure and function in DM (SA#1); to determine how the Hp-Hb complex associates with HDL and whether blocking this association can decrease HDL oxidation and improve HDL function (SA#2); and to demonstrate that HDL function can be improved in Hp 2-2 DM by antioxidants (SA#3). Results from this study will shed light on the mechanistic correlation between the Hp genotype and cardiovascular diseases associated with DM, thus promoting application of a pharmacogenomic approach to identifying patients who will benefit from antioxidative treatment.


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: 2013 ( Subtotal = $128,193 )
2013	2013	TECHNION ISRAEL INSTITUTE TECHNOLOGY	TECHNION CITY 32000	HAIFA				ISR	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	7/4/2013	EXTENSION WITH OR WITHOUT FUNDS	$128,193
														Subtotal = $128,193

Issue Date FY: 2012 ( Subtotal = $132,843 )
2012	2012	TECHNION ISRAEL INSTITUTE TECHNOLOGY	TECHNION CITY 32000	HAIFA				ISR	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	7/26/2012	NON-COMPETING CONTINUATION	$132,843
														Subtotal = $132,843

Issue Date FY: 2011 ( Subtotal = $132,843 )
2011	2011	TECHNION ISRAEL INSTITUTE TECHNOLOGY	TECHNION CITY 32000	HAIFA				ISR	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	6/23/2011	NON-COMPETING CONTINUATION	$132,843
														Subtotal = $132,843

Issue Date FY: 2010 ( Subtotal = $134,185 )
2010	2010	TECHNION-ISRAEL INSTITUTE OF TECHNOLOGY	TECHNION CITY 32000	HAIFA				ISR	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	7/12/2010	NON-COMPETING CONTINUATION	$134,185
														Subtotal = $134,185

Issue Date FY: 2009 ( Subtotal = $135,540 )
2009	2009	TECHNION-ISRAEL INSTITUTE OF TECHNOLOGY	TECHNION CITY 32000	HAIFA				ISR	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	5/1/2009	NEW	$135,540
														Subtotal = $135,540

Grand Total All Awards = $663,604

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OXIDATION HYPOTHESIS REVISITED: HAPTOGLOBIN GENOTYPE & DIABETIC ATHEROSCLEROSIS

Award Number: R01DK085226

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2009

PERIOD OF PERFORMANCE END DATE: 08/31/2014

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