The Role of MicroRNAs on Hepatic Growth and Senescence

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The relationship between accelerated postnatal catch-up growth and premature ageing is one of the important discoveries in biology. Recent studies by our laboratory and others has demonstrated that maternal protein restriction (MPR, 8% protein) during pregnancy in rats followed by rapid catch-up growth leads to premature hepatic senescence, glucose intolerance, and decreased longevity. In contrast, if there is no catch-up growth (due to maintenance of an 8% protein diet throughout life), longevity is not hindered. While we have previously demonstrated that posttranslational histone modifications may play a role in the long-term fetal programming of the liver, very little is known about the role of microRNAs (miRs) in governing hepatic function and senescence. Using Microarray analysis, we have recently identified that miR-193b, miR-29, and miR-140 are altered in the senescent livers of these MPR offspring with catch-up growth. Therefore, the overall goal of our research program is to understand the regulation and identity of miRNA targets in the liver which influence function, growth and senescence. Recently we demonstrated that (i) miR-29 expression is inversely related to insulin growth factor 1 (Igf-1) in these MPR offspring, (ii) these MPR offspring have augmented hepatic endoplasmic reticulum (ER) stress, and (iii) ER stress increases neuronal miR-29a in vivo. Therefore, our first objective is to directly assess the role of ER stress on hepatic miR-29a and other miRs in vitro using primary cultures of neonatal rat liver cells treated with and without activators of ER stress followed by measuring temporal changes in miR-29, Igf-1 expression and other miR-29 target genes. In addition, we would also inhibit miR-29 expression to observe if the silencing of Igf-1 could be prevented. Given Cyclin D1, an important component of the cell cycle, has been implicated in premature senescence and is inversely related to miR-193b expression in these MPR offspring, our second objective is to characterize if augmented Cyclin D1 is associated with impairment of other components the cell cycle. To directly implicate the role of miR-193b on Cyclin D1 and senescence in the liver, we will assess if activation of miR-193b alters Cyclin D1 expression, the cell cycle, and senescence in primary cultures of neonatal rat liver cells. Finally, given miR-140 targets HDAC-4 and SIRT1, both histone deacetylases, our third objective is to test if alterations in miR-140 in vitro influences total Histone H3 acetylation along with hepatic target genes known to be affected by histone acetylation and MPR. Collectively, these studies would further implicate miRs with impaired hepatic function, growth and aging. In addition, by using this MPR regime as a unique and highly relevant model of premature senescence, we can further elucidate how better management of low birth weight offspring can improve longevity in mammals.**