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Grant Abstract

Grant Number: 2P01HL081587-06A1
PI Name: Walsh
Project Title: Metabolic Control of Endothelias Cell Phenotype

Abstract: DESCRIPTION (provided by applicant): It is widely recognized that the endothelium is affected by the metabolic state of the organism, and endothelial function can also influence systemic metabolism. This program project renewal application brings together five productive project leaders who have a long history of collaboration to investigate mechanisms that underlie how the endothelium is both affected by and contributes to metabolic homeostasis. Project 1 will examine the mechanism by which endothelial cells switch from aerobic respiration to anaerobic glycolysis under conditions that stimulate vascular growth (i.e. hypoxia and pseudo-hypoxia) by focusing on a HIF1a-regulated microRNA that regulates the expression of mitochondrial respiratory complex proteins. Project 2 will examine mechanisms of redox regulation of cell signaling in vascular function and how these processes are perturbed by endothelial cell exposure to oxidants and reactive lipids that are associated with inflammation and metabolic disease. Project 3 will examine the functional interplay between endothelial function and inflammation in adipose tissue and assess how these processes influence systemic metabolism by focusing on mouse models that over- and under-express the adipocyte-derived cytokine adiponectin. Project 4 will also examine the interrelationship between the endothelium and inflammation in fat by measuring microvascular function and inflammatory markers in the fat of obese individuals before and after extensive weight loss resulting from bariatric surgery. Project 5 will examine the role of mitochondrial homeostasis in endothelial and inflammatory cells isolated from patients with Type 2 diabetes mellitus. This conceptually cohesive program focuses on an under-explored, yet clinically important, area of endothelial cell biology. With these proposed studies, we hope develop a better understanding of how endothelium functions at the interface of cardiovascular disease and metabolic dysfunction. (End of Abstract) INDIVIDUAL PROJECTS AND CORE UNITS: PROJECT 1: ADIPOSE TISSUE INFLAMMATION AND VASCULARITY (WALSH, KENNETH) RESUME AND SUMMARY OF DISCUSSION: This exceptional study is highly significant in that it proposes to better understand the molecular mechanism underlying adiponectin action in controlling adipose tissue inflammation and vascularity. The review committee felt that the hypothesis is strongly supported by solid preliminary data, and most approaches are available in the PI's lab. The committee also felt that the availability of the mouse models also makes the feasibility of Aim 3 high. The PI was felt to be highly productive and well-known in the field, which gave this project a high of being successful. The PI addressed all the concerns of the previous review and there were no other concerns identified. Completion of proposed study will advance adiponectin field in understanding the anti-inflammation function of adiponectin. DESCRIPTION (provided by applicant): It is becoming increasingly appreciated that adipose tissue macrophage activation plays an important role in the development of chronic inflammation and metabolic dysfunction associated with obesity. Obese organisms also display capillary rarefaction and diminished perfusion in their fat pads. Adipose tissue hypoxia is thought to be linked to inflammation because this stress will favor adipocyte necrosis and lead to macrophage recruitment. In turn, the fat pad milieu of an obese organism will favor macrophage activation and lead to further degradation of the vascular bed. Thus, it is reasonable to speculate that obesity favors a vicious cycle of hypoxia and inflammation in adipose tissue. Adiponectin is a fat-derived cytokine that has both anti-inflammatory and pro-angiogenic activities. Adipose tissues from lean organisms express high levels of adiponectin and there is a progressive decline in adiponectin expression as fat mass increases. Both inflammatory cytokines and hypoxia

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