The overall objective of new application is to determine the role and mechanism of NADPH-related oxidative stress in Hyperhomocysteinemia (HHcy)-caused monocyte differentiation and endothelial dysfunction. The hypothesis to be tested in this proposal is that HHcy causes SAH accumulation, resulting in hypomethylative epigenetic modification on NADHP oxidase gene, leading to NADPH oxidase-related oxidative stress and inflammatory MC differentiation, contributing to vascular dysfunction. This project will study this hypothesis utilizing three linked specific aims.
In Aim 1, they will characterize MC differentiation/adhesion, and vascular function/inflammation in HHcy mice.
In Aim 2, they will examine the role and mechanism of NADPH oxidase activation and epigenetic modification in Hcy-induced MC differentiation in mouse primary splenocytes.
In Aim 3, they will define the role of HHcy, SAH accumulation, DNA hypomethylation, and NADPH oxidase activation in inflammatory MC differentiation and vascular dysfunction in Tg-hCBS Cbs-/- mice. It is believed that completion of the specific aims of this proposal may provide important insights into the role of Hcy in CVD, and identify the underline mechanism.

Public Health Relevance

Increased plasma homocysteine (Hcy) level is an independent risk factor for cardiovascular diseases (CVD). However, the underlying mechanism is largely unknown. This project will illustrate mechanism by which how Hcy causes vessel wall inflammation and impair vascular function, both are early events of cardiovascular disease. We anticipate this study will identify biomarker and novel therapeutic target of cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL110764-04
Application #
8676929
Study Section
Special Emphasis Panel (ZRG1-VH-D (02))
Program Officer
Charette, Marc F
Project Start
2011-08-18
Project End
2016-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
4
Fiscal Year
2014
Total Cost
$498,009
Indirect Cost
$172,513
Name
Temple University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
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Huang, Xiao; Gong, Ren; Li, Xinyuan et al. (2013) Identification of novel pretranslational regulatory mechanisms for NF-*B activation. J Biol Chem 288:15628-40
Yin, Ying; Pastrana, Jahaira Lopez; Li, Xinyuan et al. (2013) Inflammasomes: sensors of metabolic stresses for vascular inflammation. Front Biosci (Landmark Ed) 18:638-49