This application is being submitted in response to Notice Number NOT-OD-09-058, NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications. This competitive revision application pertains to parent grant 1RO1 AG026094, The Sir2-p53-IGF link in mammalian life span control. We have identified the insulin/IGF signaling pathway as a key mediator of mammalian longevity that is subject to control by the tumor suppressor p53. Disruption of normal p53 activity results in increased expression of the IGF-1 receptor (IGF-1R) and is linked to decreased longevity and accelerated aging in mice. This increase in IGF-1R activity is apparently a direct cause of reduced longevity and accelerated aging in mice with mutant p53 activity as haploinsufficiency for the Igf-1r gene rescues life span completely. Experiments proposed under this competitive revision application aim to understand the molecular mechanism underlying increases in IGF-1R expression that can significantly impair longevity. These experiments are not covered by the specific aims of the parent grant and thus represent a significant expansion of scope. In the first supplemental specific aim (SSA), we will test the hypothesis that the IGF-1 receptor is regulated by miR-675, a microRNA encoded by the H19 gene (SSA1). Computation analysis of potential microRNA binding sites in the 3'UTR of the IGF-1R mRNA identified a highly conserved site as a target of miR-675. This site in the IGF-1R mRNA is shared by humans and non-human primates, rodents, and other vertebrates down to and including chickens. miR-675 is encoded by the H19 gene, a transcriptional target of p53. Thus, the effect of miR-675 on the level of the IGF-1R could provide a direct link between disturbances in p53 activity and life span. In the second SSA, we will test the hypothesis that deficiencies in H19 and miR-675 expression in mice reduce longevity by increasing the level of the IGF-1R (SSA 2). We will cross p44Tg mice with H19BAC mice, a strain of transgenic mice developed by Dr. Karl Pfeifer (NIH) that over-express the H19 gene. If the deficit in H19 expression in p44Tg mice is the cause of their shortened life span, restoring H19 levels to normal in p44Tg;H19BAC mice should rescue longevity. Furthermore, if the molecular mechanism we have proposed for regulation of IGF-1R translation by miR-675 is correct, then rescue of life span will be accompanied by restoration of normal levels of IGF-1R protein in p44Tg;H19BAC mice. By expanding the scope of the parent grant to include experiments to test these hypotheses, we anticipate that the requested revision will give us the opportunity to explore novel mechanisms by which central pathways regulating life span are established.
This application is being submitted in response to Notice Number NOT-OD-09-058, NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications. This competitive revision application pertains to parent grant 1RO1 AG026094, The Sir2-p53-IGF link in mammalian life span control. We have identified the insulin/IGF signaling pathway as a key mediator of mammalian longevity that is subject to control by the tumor suppressor p53. Disruption of normal p53 activity results in increased expression of the IGF-1 receptor (IGF-1R) and is linked to decreased longevity and accelerated aging in mice. Experiments proposed under this competitive revision application aim to understand the molecular mechanism underlying increases in IGF-1R expression that can significantly impair longevity. These experiments are not covered by the specific aims of the parent grant and thus represent a significant expansion of scope.
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