Apoptosis is a physiological cell death mechanism that has been shown to be involved in physiological and pathological events in man. Deregulation of apoptosis has been implicated in pathogenesis of human coronary artery disease, vascular remodeling, and vascular inflammation. We have investigated molecular biology of vascular cell apoptosis and made two significant contributions; we have discovered that massive apoptotic responsive in vascular smooth muscle cells invoke profound inflammatory response in the vessel wall, and apoptotic cells in general including the vascular smooth muscle cells utilize a novel endogenous engulfment ligand receptor system to facilitate engulfment of apoptotic cells. The discovery of the first endogenous protein ligand, annexin I, and its receptor, the phosphatidylserine receptor (PSR), was achieved by the use of high-throughput proteomic profiling technology, termed the 3-Dimensional Isotope-Coded Affinity Tags and mass spectrometry. Although significant progress has been made in the identification of a crucial ligand: receptor pair that controls apoptotic cell engulfment in the vascular cells, comprehensive understanding of signaling mechanisms associated with how apoptotic cells are recognized and internalized is lacking. The long-term objectives of this competitive renewal application is to study the molecular biology and associated functions of PSR, its control mechanisms, its interacting protein complexes, and the function properties of PSR associating proteins. We will utilize proteomics technologies that are established in the laboratory together with traditional biochemical, immunological, imaging, tissue culture models of vascular cells, and genetics model system. Specifically, we will study the basic mechanisms of PSR mediated apoptotic cell recognition, PSR mediated signaling events, interactions of PSR and other receptors in response to apoptotic cells and to chemo-attractants secreted by the apoptotic cells, signaling-dependent interactions of PSR and cytosolic signaling molecules, and elucidate the mechanisms of how PSR mediates the overall apoptotic cell engulfment. The proposed studies are anticipated to provide novel insights into the molecular biology of how apoptotic cells are recognized and cleared in the vessel wall to prevent vascular inflammation.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Rabadan-Diehl, Cristina
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Connecticut
Anatomy/Cell Biology
Schools of Medicine
United States
Zip Code
Rezaul, Karim; Murphy, Michael; Lundgren, Deborah H et al. (2010) Combined mass spectrometry- and immunohistochemistry-based approach to determine protein expression in archival melanoma--proof of principle. Pigment Cell Melanoma Res 23:849-52
Lundgren, Deborah H; Hwang, Sun-Il; Wu, Linfeng et al. (2010) Role of spectral counting in quantitative proteomics. Expert Rev Proteomics 7:39-53
Mayya, Viveka; Lundgren, Deborah H; Hwang, Sun-Il et al. (2009) Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions. Sci Signal 2:ra46
Mayya, Viveka; Han, David K (2009) Phosphoproteomics by mass spectrometry: insights, implications, applications and limitations. Expert Rev Proteomics 6:605-18
Wu, Linfeng; Hwang, Sun-Il; Rezaul, Karim et al. (2007) Global survey of human T leukemic cells by integrating proteomics and transcriptomics profiling. Mol Cell Proteomics 6:1343-53
Bagnato, Carolina; Thumar, Jaykumar; Mayya, Viveka et al. (2007) Proteomics analysis of human coronary atherosclerotic plaque: a feasibility study of direct tissue proteomics by liquid chromatography and tandem mass spectrometry. Mol Cell Proteomics 6:1088-102
Choudhary, Dharamainder; Jansson, Ingela; Rezaul, Karim et al. (2007) Cyp1b1 protein in the mouse eye during development: an immunohistochemical study. Drug Metab Dispos 35:987-94
Hwang, S-I; Thumar, J; Lundgren, D H et al. (2007) Direct cancer tissue proteomics: a method to identify candidate cancer biomarkers from formalin-fixed paraffin-embedded archival tissues. Oncogene 26:65-76
Hwang, Sun-Il; Lundgren, Deborah H; Mayya, Viveka et al. (2006) Systematic characterization of nuclear proteome during apoptosis: a quantitative proteomic study by differential extraction and stable isotope labeling. Mol Cell Proteomics 5:1131-45
Wu, Linfeng; Han, David K (2006) Overcoming the dynamic range problem in mass spectrometry-based shotgun proteomics. Expert Rev Proteomics 3:611-9

Showing the most recent 10 out of 17 publications