Mechano-biologic Determinants of AAA Disease

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DESCRIPTION (provided by applicant): 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.