The overall goal of this research program is to gain insight into the common cellular and molecular mechanisms through which reactive oxygen species (ROS) and inflammation individually and together mediate normal vascular function and vascular disease. While ROS are required for normal metabolic function and cell viability, excessive ROS or weakened antioxidant defenses can lead to pathophysiological events. Similarly, while monocytes and macrophages mediate healing and new vessel formation, excess inflammation contributes to atherosclerosis and hypertension. Over the past 25 years, our research group has investigated the myriad responses to ROS production and inflammation in the vasculature and studied their roles in virtually all of the major vascular diseases. In this proposal, we will expand upon these findings to better understand the mechanisms by which ROS and inflammation are both necessary and detrimental to vascular function, and to begin to explore therapeutic strategies for targeted intervention. In Project 1, Dr. Hanjoong Jo will explore the mechanisms responsible for, and consequences of, downregulation of bone morphogenic receptor II (BMPR2) by pro-atherogenic microRNAs and will develop target site blockers that can protect BMPR2 from downregulation. In Project 2, Dr. Aloke Finn will study a new type of non-foam cell macrophage, M(Hb) or Hb- associated macrophage, that expresses CD163. He will test the hypothesis that these novel macrophages induce plaque angiogenesis and increase macrophage survival, promoting the development of high-risk plaques. In Project 3, Dr. Kathy Griendling will examine the functional and structural aspects of the Nox4- associated protein, Poldip2, that contribute to matrix regulation and aortic stiffening, and will tst targeted therapeutic strategies to prevent aneurysm formation. Dr. Alejandra San Martin is also studying Poldip2 in Project 4, but with an eye to understanding its role in mitochondrial dynamics and proliferation. Finally, in Project 5, Dr. W. Robert Taylor will investigate how the expression of catalase, a critically important antioxidant enzyme that modulates wall stiffness and aneurysm formation, is regulated by the PGC-1a pathway or polymorphisms, and will test inhibitors of catalase expression for their efficacy in treating aneurysms. The proposed studies will be supported by the exceptional collaborative expertise of Dr. Lula Hilenski, the director of the Microscopy in Medicine Core, and Dr. Bernard Lassgue, director of the Animal Core. While the major goal of the program is centered on understanding basic mechanisms of disease and beginning to translate them into clinically relevant applications, we are also dedicated to trainin the next generation of investigators, supporting the careers of junior faculty, and disseminating our findings to serve as a nidus for future investigation. This PPG application thus represents a distinctive multidisciplinary collaboration among highly qualified scientists with extensive experience in oxidative stress, inflammation and vascular biology who remain committed to defining the pathophysiologic basis of vascular disease.

Public Health Relevance

Most, if not all, cardiovascular diseases are caused in part by excess reactive oxygen species and inflammation of the blood vessel wall. Treating these two processes is difficult because both also serve protective functions in the vasculature. The projects included in the program are all designed to better understand how specific proteins regulate, or are regulated by, reactive oxygen species and inflammation, with the goal of developing novel targeted therapeutic strategies for atherosclerosis, aneurysm formation and aortic stiffening, while preserving and enhancing the formation of new blood vessels in response to ischemia. (End of Abstract) INDIVIDUAL PROJECTS AND CORE UNITS PROJECT 1: ANTI-ATHEROGENIC AND ANTI-INFLAMMATORY ROLE OF BONE MORPHOGENIC PROTEIN RECEPTOR II (JO, HANJOONG)

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL095070-10
Application #
9692779
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Hasan, Ahmed a K
Project Start
2008-12-01
Project End
2020-10-31
Budget Start
2019-05-01
Budget End
2020-10-31
Support Year
10
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Emory University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Paredes, Felipe; Suster, Izabela; Martin, Alejandra San (2018) Poldip2 takes a central role in metabolic reprograming. Oncoscience 5:130-131
Lee, Grace Sanghee; Salazar, Hector F; Joseph, Giji et al. (2018) Osteopontin isoforms differentially promote arteriogenesis in response to ischemia via macrophage accumulation and survival. Lab Invest :
Simmons, Craig A; Jo, Hanjoong (2018) Editorial: Special Issue on Heart Valve Mechanobiology : New Insights into Mechanical Regulation of Valve Disease and Regeneration. Cardiovasc Eng Technol 9:121-125
Williams, Holly C; Ma, Jing; Weiss, Daiana et al. (2018) The cofilin phosphatase slingshot homolog 1 restrains angiotensin II-induced vascular hypertrophy and fibrosis in vivo. Lab Invest :
Yeligar, Samantha M; Kang, Bum-Yong; Bijli, Kaiser M et al. (2018) PPAR? Regulates Mitochondrial Structure and Function and Human Pulmonary Artery Smooth Muscle Cell Proliferation. Am J Respir Cell Mol Biol 58:648-657
Vukelic, Sasa; Xu, Qian; Seidel-Rogol, Bonnie et al. (2018) NOX4 (NADPH Oxidase 4) and Poldip2 (Polymerase ?-Interacting Protein 2) Induce Filamentous Actin Oxidation and Promote Its Interaction With Vinculin During Integrin-Mediated Cell Adhesion. Arterioscler Thromb Vasc Biol 38:2423-2434
Hernandes, Marina S; Lass├Ęgue, Bernard; Hilenski, Lula L et al. (2018) Polymerase delta-interacting protein 2 deficiency protects against blood-brain barrier permeability in the ischemic brain. J Neuroinflammation 15:45
Okwan-Duodu, Derick; Hansen, Laura; Joseph, Giji et al. (2018) Impaired Collateral Vessel Formation in Sickle Cell Disease. Arterioscler Thromb Vasc Biol 38:1125-1133
Hu, Shuhong; Liu, Yifei; You, Tao et al. (2018) Vascular Semaphorin 7A Upregulation by Disturbed Flow Promotes Atherosclerosis Through Endothelial ?1 Integrin. Arterioscler Thromb Vasc Biol 38:335-343
Heath, Jack M; Fernandez Esmerats, Joan; Khambouneheuang, Lucky et al. (2018) Mechanosensitive microRNA-181b Regulates Aortic Valve Endothelial Matrix Degradation by Targeting TIMP3. Cardiovasc Eng Technol 9:141-150

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