This revised renewal application, consisting of 5 scientific components and 2 core facilities, will define the mechanisms involved in thrombo-atherosclerosis. Through continued active collaborations, we will test the hypothesis that soluble mediators (e.g. nitrogen oxides, reactive oxygen species, growth factors) regulate vascular cell reactivity.
Our aims focus on interactions between hematologic and vascular cells to define the: effects of fluid-phase and cell-associated thromboregulators (ectoADPase/CD39;nitric oxide (NO);eicosanoids on vascular and blood cell reactivity;regulation of the annexin 2 stress responses to vascular perturbation;growth factor regulation of adaptive vascular remodeling in neo-angiogenesis;subcellular regulation of eNOS activity in endothelial cells;and, the modulation of cyclooxygenase by nitrogen oxides including their impact on atherogenesis. Through the support of this PPG during the last 5 years, we discovered: 1) the ecto ADPase is the major thromboregulator of the vasculature, 2) annexin 2 is a key regulator of fibrin homeostasis and vascular remodeling, 3) neurotropins are critical modulators of angiogenesis and atherogenesis, 4) the role of pterin oxidation and structural elements of eNOS which regulate NO and peroxynitrite production, and 5) NO and peroxynitrite alter cyclooxygenase structure which impacts on inflammation. In this revised proposal, we carefully addressed each of the Reviewers specific concerns by providing new data or designing new experiments per their request. The SRC felt that the strengths of the Program outweigh any weaknesses, and that the program itself consisted of outstanding project leaders, who designed novel experiments, making it a program of significance. This program takes advantage of the complementary research expertise of our vascular biology group to promote continued synergistic interactions. Our on-going collaborative efforts, where our PPG Vascular Biology group has published over 90 research papers during the past 5 years, coupled with our major scientific discoveries, underscores the success of this program. As a testament to our achievements, Cornell Medical College established a Center of Vascular Biology headed by Dr. David Hajjar. Institutional funds (>$5.0 million) have been designated for capital improvements, equipment, and faculty development to support this program.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL046403-18
Application #
7626772
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Srinivas, Pothur R
Project Start
1997-08-01
Project End
2012-01-31
Budget Start
2009-02-01
Budget End
2010-01-31
Support Year
18
Fiscal Year
2009
Total Cost
$2,545,200
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Ramakrishnan, Devi Prasadh; Hajj-Ali, Rula A; Chen, Yiliang et al. (2016) Extracellular Vesicles Activate a CD36-Dependent Signaling Pathway to Inhibit Microvascular Endothelial Cell Migration and Tube Formation. Arterioscler Thromb Vasc Biol 36:534-44
Hajjar, Katherine A (2015) The Biology of Annexin A2: From Vascular Fibrinolysis to Innate Immunity. Trans Am Clin Climatol Assoc 126:144-55
Dassah, Maryann; Almeida, Dena; Hahn, Rebecca et al. (2014) Annexin A2 mediates secretion of collagen VI, pulmonary elasticity and apoptosis of bronchial epithelial cells. J Cell Sci 127:828-44
Anastasia, Agustin; Deinhardt, Katrin; Wang, Shiyang et al. (2014) Trkb signaling in pericytes is required for cardiac microvessel stabilization. PLoS One 9:e87406
Abbott, Geoffrey W; Tai, Kwok-Keung; Neverisky, Daniel L et al. (2014) KCNQ1, KCNE2, and Na+-coupled solute transporters form reciprocally regulating complexes that affect neuronal excitability. Sci Signal 7:ra22
Hajjar, David P; Gotto Jr, Antonio M (2013) Biological relevance of inflammation and oxidative stress in the pathogenesis of arterial diseases. Am J Pathol 182:1474-81
Kennedy, David J; Chen, Yiliang; Huang, Wenxin et al. (2013) CD36 and Na/K-ATPase-?1 form a proinflammatory signaling loop in kidney. Hypertension 61:216-24
Zhou, Ming-Sheng; Chadipiralla, Kiranmai; Mendez, Armando J et al. (2013) Nicotine potentiates proatherogenic effects of oxLDL by stimulating and upregulating macrophage CD36 signaling. Am J Physiol Heart Circ Physiol 305:H563-74
Luo, Min; Hajjar, Katherine A (2013) Annexin A2 system in human biology: cell surface and beyond. Semin Thromb Hemost 39:338-46
Siao, Chia-Jen; Lorentz, Christina U; Kermani, Pouneh et al. (2012) ProNGF, a cytokine induced after myocardial infarction in humans, targets pericytes to promote microvascular damage and activation. J Exp Med 209:2291-305

Showing the most recent 10 out of 226 publications