The purpose of these studies is to determine the role of signaling through the growth hormone (GH) and IGF-I receptors (IGF-IR) in mediating changes in vascular aging in mice and in altering the development of neointima in response to injury. The studies will utilize mice that are either haploinsufficient for the IGF-IR or have complete elimination of the GH receptor to determine how these changes alter longevity and/or vascular aging. Smooth muscle cells (SMC) obtained from the mice that are IGF-IR (+/-) will be analyzed for changes in responsiveness both to IGF-I and to changes integrin ligand occupancy. Cells from young and old animals will be compared to determine whether these responses are altered and whether reduced IGF-I signaling alters this age-dependent change. The specific pathways to be examined will include IGF-I activation of PI-3 kinase and MAP kinase. The tyrosine phosphatase SHP-2 will be analyzed to determine whether its role in mediating IGF-I signaling is altered under these conditions. The ability of IGF-I to suppress forkhead transcription factor activity and to regulate the activation of small heatshock proteins will be examined. If defects are detected in the interaction between extracellular matrix protein stimulated signaling through the alphaVbeta3 receptor and IGF-I signaling then whether these changes lead to alterations in heatshock protein activation will be determined. Since IGF-I is known to alter SMC differentiation the propensity of cells that have reduced IGF-IR to dedifferentiate and whether their response to ECM protein modulation of differentiation is altered will be determined. Additional studies will address whether the response to vascular injury is altered in animals with reduced IGF-IR. The responses of chaperones and regulators of reactive oxygen species formation will be determined. Likewise the ability of cells that express lower IGF-IR to respond to a chronic injury such as hypercholesterolemia will be determined. Lesion morphometry will be calculated in animals that are IGF-IR (+/-) and APOE (-/-) and compared to IGF-IR (-/+) animals at both 4 and 16 months of age. Alterations that have occurred in chaperones and ROS protein function following this chronic injury stimulus will be documented and it will be determined if reduced IGF-I signaling is leading to a change in the ability in these systems to adapt to the chronic injury stimulus. In this manner we should be able to determine the interactions that occur among these three important signaling systems and how they are altered during vascular injury.
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| Ren, Hong Yu; Patterson, Cam; Cyr, Douglas M et al. (2011) Reconstitution of CHIP E3 ubiquitin ligase activity. Methods Mol Biol 787:93-103 |
| Aitsebaomo, Julius; Srivastava, Siddharth; Zhang, Hua et al. (2011) Recombinant human interleukin-11 treatment enhances collateral vessel growth after femoral artery ligation. Arterioscler Thromb Vasc Biol 31:306-12 |
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