Little is known about the role of glycosphingoiipids (GSL) in atherosclerosis, which contributes to cardiovascular disease (CVD) and death in ~50% of the population, in the western world. We have observed that the level of a GSL;lactosylceramide (LacCer) and the activity of LacCer synthase (LCS) is increased in human atherosclerotic plaques, as compared to visibly normal tissue. Our preliminary studies also show that atherosclerosis and a marked increase in the level of blood cholesterol can be reveresed by a GSL synthesis inhibitor (D-1-phenyl-2-decanoylamino-3-morpholino-1-propanol;D-PDMP) in a dietary model of hyperlipidemia in rabbits. Our overall goal is to determine whether inhibiting GSL synthesis can ameliorate atherosclerosis in an apolipoprotien E(apoE-/-) mouse model of hyperlipidemia /atherosclerosis. And to determine whether LCS mass can serve as a prognostic marker in CVD.
Our specific aims are: 1. To determine the efficacy of D-PDMP in regulating atherosclerosis in apoE-/- mice; herein, the efficacy of D-PDMP in preventing and interfering with atherosclerosis will be examined in mice fed a hyperlipidemic diet, and the following will be measured: cadiac function, carotid intima media thickeness, arterial stiffness, and lipid and lipoprotiens. 2. To determine the molecular mechansim(s) by which D-PDMP regulates atherosclerosis;proteins affecting GSL and cholesterol homeostasis contributing to cell proliferation adhesion and angiogenesis will be measured. 3.To determine the specific roles of Lactosylceramide and LCS in atherosclerosis. We will synthesize novel LCS inhibitors and determine their efficacy in preventing /interfering with atherosclerosis. 4. Quantify the mass of LCS and assess post- transcriptional modification in the heart and artery in normal and atherosclerotic mice. We will develop novel ELISA assays and use mass spectrometry to determine LCS mass and post transcriptional modifiactions. The proposed studies will definitely establish that inhibiting GSL synthesis can inhibit atherosclerosis. It will also prove that LCS can be a novel target for developming drugs to ameliorate CVD and related diseases. Finally, these studies will change our mind-set with regard to the role of GSL in health and CVD.

Public Health Relevance

Although much is known about the role of cholesterol in heart disease, our knowledge about the role of glycosphingoiipids in this disease has lagged behind. Herein, we propse to test the hypothesis that inhibiting glycosphingolipid synthesis can decrease blood levels of cholesterol, and ameliorate atherosclerosis and heart disease in animal models. Our studies will lay the foundation for application of novel drug therapy to amfillnratft hfiart riisfiasft in man

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL107153-03
Application #
8477278
Study Section
Special Emphasis Panel (ZHL1-CSR-H)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
3
Fiscal Year
2013
Total Cost
$280,169
Indirect Cost
$109,334
Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Harosh-Davidovich, Shani Ben; Khalaila, Isam (2018) O-GlcNAcylation affects ?-catenin and E-cadherin expression, cell motility and tumorigenicity of colorectal cancer. Exp Cell Res 364:42-49
Drake, Walter R; Hou, Ching-Wen; Zachara, Natasha E et al. (2018) New use for CETSA: monitoring innate immune receptor stability via post-translational modification by OGT. J Bioenerg Biomembr 50:231-240
Höti, Naseruddin; Yang, Shuang; Hu, Yingwei et al. (2018) Overexpression of ? (1,6) fucosyltransferase in the development of castration-resistant prostate cancer cells. Prostate Cancer Prostatic Dis 21:137-146
Hashimoto, Toru; Kim, Grace E; Tunin, Richard S et al. (2018) Acute Enhancement of Cardiac Function by Phosphodiesterase Type 1 Inhibition. Circulation 138:1974-1987
Rainer, Peter P; Dong, Peihong; Sorge, Matteo et al. (2018) Desmin Phosphorylation Triggers Preamyloid Oligomers Formation and Myocyte Dysfunction in Acquired Heart Failure. Circ Res 122:e75-e83
Groves, Jennifer A; Zachara, Natasha E (2017) Characterization of tools to detect and enrich human and mouse O-GlcNAcase. Glycobiology :
Yang, Shuang; Hu, Yingwei; Sokoll, Lori et al. (2017) Simultaneous quantification of N- and O-glycans using a solid-phase method. Nat Protoc 12:1229-1244
Yang, Weiming; Shah, Punit; Hu, Yingwei et al. (2017) Comparison of Enrichment Methods for Intact N- and O-Linked Glycopeptides Using Strong Anion Exchange and Hydrophilic Interaction Liquid Chromatography. Anal Chem 89:11193-11197
Grima, Jonathan C; Daigle, J Gavin; Arbez, Nicolas et al. (2017) Mutant Huntingtin Disrupts the Nuclear Pore Complex. Neuron 94:93-107.e6
Groves, Jennifer A; Maduka, Austin O; O'Meally, Robert N et al. (2017) Fatty acid synthase inhibits the O-GlcNAcase during oxidative stress. J Biol Chem 292:6493-6511

Showing the most recent 10 out of 137 publications