The translation of the sickle mutation into clinical disease involves and exceedingly complex pathophysiology. This Program is based on the concepts that vascular endothelial cell biology is central to the vascular pathobiology of sickle disease, and that sickle disease comprises an inflammatory state with abnormal endothelial cell activation/dysfunction: This Program focuses on important issues related to these concepts. Technologies employed range from physiology and clinical investigation, to cellular biology and biochemistry, to molecular biology. The Program has three cores: Administrative (A), Cell Culture (B), and Transgenic Mouse (C). Project 1 focuses on abnormal tissue factor expression by pulmonary vein endothelium, and the roles of inflammation and NO and reperfusion injury in this process. Studies to be done will include use of various knockout states bred into the sickle animal, as well as specific cell types isolated from knockout mice. Project 2 examines white blood cell interaction with the endothelium in the live sickle transgenic mouse. The role of sickling in causing inflammation will be evaluated, and the role of adhesive white cells in causing secondary red cell occlusion will be studies. Roles of NO and prostaglandin will be defined. Project 3 will use a model of regional ischemia (kidney) to study the process by which hemeoxygenase- 1 (HO1) modifies response to ischemia, looking at adaptive and maladaptive changes. Studies to be done will include use of mice with conditional HO1 knockout state. Project 5 focuses on the role of HO1 in modulating vascular stasis in the sickle mouse. Studies to be done include use of the HO1 overexpressing sickle mouse. In conducting these Projects, our overarching objective is to achieve a greater understanding of disease pathobiology as a path to identifying novel therapeutic approaches to this disease. Lay Summary: Sickle disease is a severe disease that causes premature death and many health problems. Our studies are designed to understand how this disease works. We believe that the results of our proposed studies will directly lead to new treatments for sickle patients.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL055552-15
Application #
8141225
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Luksenburg, Harvey
Project Start
1997-09-01
Project End
2013-08-31
Budget Start
2011-09-01
Budget End
2013-08-31
Support Year
15
Fiscal Year
2011
Total Cost
$1,932,122
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Solovey, Anna; Somani, Arif; Belcher, John D et al. (2017) A monocyte-TNF-endothelial activation axis in sickle transgenic mice: Therapeutic benefit from TNF blockade. Am J Hematol 92:1119-1130
Belcher, John D; Chen, Chunsheng; Nguyen, Julia et al. (2014) Heme triggers TLR4 signaling leading to endothelial cell activation and vaso-occlusion in murine sickle cell disease. Blood 123:377-90
Schaer, Dominik J; Buehler, Paul W; Alayash, Abdu I et al. (2013) Hemolysis and free hemoglobin revisited: exploring hemoglobin and hemin scavengers as a novel class of therapeutic proteins. Blood 121:1276-84
Nath, Karl A; Grande, Joseph P; Farrugia, Gianrico et al. (2013) Age sensitizes the kidney to heme protein-induced acute kidney injury. Am J Physiol Renal Physiol 304:F317-25
Mulrooney, Daniel A; Ness, Kirsten K; Huang, Sujuan et al. (2013) Pilot study of vascular health in survivors of osteosarcoma. Pediatr Blood Cancer 60:1703-8
Weber, M L; Chen, C; Li, Y et al. (2013) Morphine stimulates platelet-derived growth factor receptor-? signalling in mesangial cells in vitro and transgenic sickle mouse kidney in vivo. Br J Anaesth 111:1004-12
Juskewitch, Justin E; Knudsen, Bruce E; Platt, Jeffrey L et al. (2012) LPS-induced murine systemic inflammation is driven by parenchymal cell activation and exclusively predicted by early MCP-1 plasma levels. Am J Pathol 180:32-40
Nath, Karl A (2012) Human AKI and heme oxygenase-1. J Am Soc Nephrol 23:971-4
Martin, Fernando L; McKie, Paul M; Cataliotti, Alessandro et al. (2012) Experimental mild renal insufficiency mediates early cardiac apoptosis, fibrosis, and diastolic dysfunction: a kidney-heart connection. Am J Physiol Regul Integr Comp Physiol 302:R292-9
Cain, David M; Vang, Derek; Simone, Donald A et al. (2012) Mouse models for studying pain in sickle disease: effects of strain, age, and acuteness. Br J Haematol 156:535-44

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