Our long term goal is to identify molecular mechanisms for the onset of accelerated atherosclerosis in diabetes mellitus. This will be accomplished by studying animal models susceptible to both diabetes and atherosclerosis. During the previous grant period, we developed new mouse models, which show remarkable changes at the artery wall due to diabetes. BALB and BALB.LDLR-/- mice develop vascular lesions which are accelerted by hyperglycemia but are independent of changes in plasma lipids. In contrast, C57BL/6 and C57BL/6.LDLR-/- develop lesions which are not reflective of hyperglycemia. We use this genetic difference to test the hypothesis that hyperglycemia modulates the expression and/or function of specific genes causing diabetic macrovascular disease, in three aims:
Aim 1 : Identify major gene(s) determining the increased atherosclerosis in response to hyperglycemia. We use microarray technology coupled to mouse genetics for validation to identify such genes.
Aim 2 : Determine the role of specific candidate gene pathways in diabetic vascular disease. We study candidate proteins of perlecan, MMP-9 and MMP-13, and connexins 43 and 45 in our mouse system.
Aim 3 : Determine whether interventions aimed at reducing oxidative stress or protease activity can protect BALB from diabetic vascular disease. Anti-oxidant diets and diets containing synthetic protease ihibitors are used to test the general role of these pathways in diabetic vascular disease. Together, this information will provide potential gene targets for future prediction and treatment of diabetic macrovascular disease in humans

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL052848-07
Application #
6654928
Study Section
Special Emphasis Panel (ZRG1-REN (01))
Program Officer
Rabadan-Diehl, Cristina
Project Start
1997-02-01
Project End
2006-08-31
Budget Start
2003-09-01
Budget End
2004-08-31
Support Year
7
Fiscal Year
2003
Total Cost
$334,294
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195
Li, Yu-I; Elmer, Gary; Leboeuf, Renee C (2008) Tanshinone IIA reduces macrophage death induced by hydrogen peroxide by upregulating glutathione peroxidase. Life Sci 83:557-62
Kanter, Jenny E; Johansson, Fredrik; LeBoeuf, Renee C et al. (2007) Do glucose and lipids exert independent effects on atherosclerotic lesion initiation or progression to advanced plaques? Circ Res 100:769-81
Tannock, Lisa R; Kirk, Elizabeth A; King, Victoria L et al. (2006) Glucosamine supplementation accelerates early but not late atherosclerosis in LDL receptor-deficient mice. J Nutr 136:2856-61
O'Brien, Kevin D; McDonald, Thomas O; Kunjathoor, Vidya et al. (2005) Serum amyloid A and lipoprotein retention in murine models of atherosclerosis. Arterioscler Thromb Vasc Biol 25:785-90
McMillen, Timothy S; Heinecke, Jay W; LeBoeuf, Renee C (2005) Expression of human myeloperoxidase by macrophages promotes atherosclerosis in mice. Circulation 111:2798-804
Ladiges, Warren C; Knoblaugh, Sue E; Morton, John F et al. (2005) Pancreatic beta-cell failure and diabetes in mice with a deletion mutation of the endoplasmic reticulum molecular chaperone gene P58IPK. Diabetes 54:1074-81
Muhlfeld, Anja S; Spencer, Min W; Hudkins, Kelly L et al. (2004) Hyperlipidemia aggravates renal disease in B6.ROP Os/+ mice. Kidney Int 66:1393-402
Shultz, Jennifer M; Zhu, Xiao Dong; Knopp, Robert H et al. (2004) Norgestimate and medroxyprogesterone acetate do not attenuate the atheroprotective effects of 17beta-estradiol in ovariectomized, apolipoprotein E-deficient mice. Fertil Steril 82 Suppl 3:1133-9
Vidal, J; Verchere, C Bruce; Andrikopoulos, S et al. (2003) The effect of apolipoprotein E deficiency on islet amyloid deposition in human islet amyloid polypeptide transgenic mice. Diabetologia 46:71-9
Schreyer, Sandra A; Lystig, Theodore C; Vick, Cynthia M et al. (2003) Mice deficient in apolipoprotein E but not LDL receptors are resistant to accelerated atherosclerosis associated with obesity. Atherosclerosis 171:49-55

Showing the most recent 10 out of 23 publications