EXCEED THE SPACE PROVIDED. Advanced age is a major risk factor for cardiovasculardisease, which remains the leading cause of death in the aged population. Aging is associated with impairments in ischemia-induced neovascularization, which occurs via two pathways: angiogenesis (sprouting of existing vessels) and vasculogenesis (denovo vessel formation by circulating endothelial progenitorcells, or EPCs). Our long term goal is to understandthe mechanisms of vasculogenesis, thereby providing rationaltherapeutic strategiesfor augmenting or preventing neovascularizationin aged or disease states. We have recently demonstrated that stromal cell-derived factor-1 (SDF-I) is selectively expressed at sites of ischemialinjuryvia the transcription factor HIF-1, and is a critical determinant of EPC trafficking and recruitmentduring vasculogenesis. In addition, recent studies have demonstrated that HlF-1 activity is markedly diminished during the aging process. Thus, it is our hypothesisthat traffickingof vascular progenitorlstem cells to sites of injury is impaired during aging because of a failure to upregulate HIF-induced SDF-1 expression in response to an ischemicstimulus. We believe that these acquired deficits in stem cell trafficking rather than stem cell depletion are responsiblefor the normal vascular changes that occur during aging and may account for the increased incidence of vascular disease in the aged population. In this proposal, Specific Aim Iwill establish the physiologic role of HIF- induced SDF-1 expressionin mediating normal progenitortrafficking using a gene targeting approach.
In Specific Aim 2, we will determine how this normaltrafficking mechanism is affected by aging, specificallyexamining the contributions of both the environment (soil) and progenitor cell function (seed) in an animal model.
In Specific Aim 3, we will perform reliable assays of cellular function in human subjects examining both soil and seed to determine the relative contributionslimpairmentsof each to stem cell trafficking in the aged. This will define normative data for stem cell trafficking in healthy aging and correlate possible deficiencies in these functions with age-related vascular disease. Finally, in Specific Aim 4 we will investigatethe use of genetically modified endothelial progenitor cells as ischemia- targeted agents to restore SDF-1 expression and normalize EPC trafficking, thereby augmenting blood vessel growth and restoring neovascularization in aged subjects. We believe that understanding age related defects in stem cell traffickingwill be importantfor the designof rationaltherapeutics to preventand treat vascular aging. PERFORMANCESITE( ========================================Section End===========================================
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