Abdominal aortic aneurysm (AAA) disease is a common and lethal health problem of older Americans. Substantial evidence links sedentary existence and resulting pro-inflammatory aortic hemodynamic conditions to the pathogenesis of AAA disease. Insights derived from in vivo imaging studies in high risk human subjects, AAA patients and animal models are essential to realizing our LONG TERM OBJECTIVE; the discovery and validation of physical and pharmacological interventions capable of reducing AAA risk, progression and treatment morbidity. We have 2 SPECIFIC AIMS: First, we will define rest and exercise aortic conditions in ambulatory subjects, patients with small, early AAA and murine models, as well as resting conditions in sedentary patients at high risk for AAA disease (spinal cord injury). These studies will test our hypotheses that I) chronically reduced flow and shear account for increased AAA risk in sedentary patients, ii) exercise improves hemodynamic conditions in small AAA, and III) variable flow models reproduce to scale clinically relevant ranges of hemodynamic conditions. Second, we will track inflammatory cell migration and gene expression in vivo in response to variable flow conditions. These experiments will define how flow loading and accompanying increased shear and tensile forces reduce macrophage delivery, accumulation, proinflammatory gene expression and progenitor cell localization and differentiation. To ACHIEVE THESE AIMS, we will analyze and define human and murine aortic hemodynamic conditions using magnetic resonance (MR) imaging and computer simulations. Hemodynamic influences on macrophage migration, accumulation and regulatory gene expression will be assayed via bioluminescence and MR cellular imaging. Circulating progenitor cell localization and differentiation will be examined via dual staining strategies in chimeric mice.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL064338-07
Application #
7258359
Study Section
Bioengineering, Technology and Surgical Sciences Study Section (BTSS)
Program Officer
Wassef, Momtaz K
Project Start
1999-09-30
Project End
2009-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
7
Fiscal Year
2007
Total Cost
$265,617
Indirect Cost
Name
Stanford University
Department
Surgery
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
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Dua, Monica M; Miyama, Noriyuki; Azuma, Junya et al. (2010) Hyperglycemia modulates plasminogen activator inhibitor-1 expression and aortic diameter in experimental aortic aneurysm disease. Surgery 148:429-35
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O'Connell, Mary K; Murthy, Sushila; Phan, Samson et al. (2008) The three-dimensional micro- and nanostructure of the aortic medial lamellar unit measured using 3D confocal and electron microscopy imaging. Matrix Biol 27:171-81

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