Life-history trade-offs have been well-documented within the literature through correlational and experimental studies. However, the physiological mechanisms underlying these trade-offs are less understood. Currently, there is great interest in shared mechanisms, specifically endocrine mechanisms, that might underlie the variation in life-history traits. Insulin-like growth factor-1 (IGF-1) may be one shared mechanism that is particularly important. IGF-1 is a metabolic hormone that is part of a highly conserved insulin-signaling pathway known to influence multiple life-history traits including growth and longevity across taxa, however, little is known about these trade-offs outside of laboratory populations. This dissertation focuses on the role of IGF-1 as a hormonal mechanism underlying the life-history trade-off between growth and aging in wild birds. While the causes of aging are not fully understood, telomere dynamics (length and change in length) are a potentially important mechanism underlying lifespan. To investigate the role of IGF-1 as a hormonal mechanism underlying the life-history trade-off between growth and aging in Franklin’s gulls (Leucophaeus pipixcan) and house sparrows (Passer domesticus). In Franklin’s gulls, dietary restriction reduced growth rate and IGF-1 levels but did not impact telomere dynamics. However, there was a significant negative correlation between IGF-1 levels and telomere length at the end of the post-natal growth period. In house sparrows, we found that nestling growth rates varied with respect to year, but IGF-1 levels did not. Telomere dynamics were not related to growth rates or IGF-1 levels, suggesting that during post-natal growth nestlings may be able to mitigate or even delay costs to later life stages. Finally, when exogenous IGF-1 was administered to house sparrow nestlings during the post-natal growth period, nestling growth was impacted but only in some years. Exogenous IGF-1 increased growth and final mass in 2016 and final mass in 2018. There was a trend suggesting experimental birds had shorter telomeres in 2016. Similarly, in 2018, experimental birds had significantly shorter telomeres than control birds. These effects were not observed in 2017, suggesting that trade-offs between growth an aging might only be visible under certain environmental conditions, which may vary with respect to year.

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Visceral adipose tissue (AT) mass increases risk for cardiovascular disease and diabetes. Glucocorticoids (GCs) cause preferential expansion of visceral compared to subcutaneous AT through poorly understood mechanisms. GCs are necessary for adipogenesis, the differentiation of adipose stem cells (ASCs) to mature adipocytes. However, this process may be impaired in visceral depots. Insufficient adipogenesis can lead to excessive hypertrophy of existing adipocytes. This hypertrophic expansion increases cell death and inflammation, driving AT dysfunction. To better understand the genes and pathways by which high GCs cause preferential expansion of visceral fat we performed transcriptomic profiling (microarray) on paired samples of visceral (Omental, Om) and abdominal subcutaneous (Abdsc) AT explants cultured with the GC receptor agonist, dexamethasone (Dex), for 7 days. Gene set enrichment analysis showed the transforming growth factor beta (TGFβ) signaling pathway, most notably the secreted anti-adipogenic factors, TGFβ and activin A, was highly enriched in Om and suppressed less by Dex. We hypothesized that Om AT and ASCs secrete factors that inhibit adipogenesis in an autocrine/paracrine manner. Conditioned media (CM) from Om tissue and ASCs suppressed differentiation by 70-80% compared to control; Dex attenuated this anti-adipogenic effect. Both TGFβ and activin A levels were 4-5 fold higher in CM from Om compared to Abdsc ASCs. Both factors signal via cell surface receptors that increase SMAD2 phosphorylation (P-SMAD2), basal levels of which were 3-4 fold higher in Om ASCs. Additionally, CM from Om ASCs increased P-SMAD2. siRNA mediated knockdown of activin A improved differentiation of Om ASCs, but did not reach levels observed in Abdsc. Blocking TGFβ and activin A signaling using SB431542 robustly increased adipogenesis of Om ASCs and prevented the anti-adipogenic effect of CM. GCs decreased production of TGFβ and activin A, but both remained higher in OmCM. Overnight Dex treatment decreased P-SMAD2 and increased the expression of the TGFβ co-receptor, TGFBR3, which decreases TGFβ signaling, in Abdsc ASCs. GCs failed to decrease P-SMAD2 and increased TGFBR3 in Om ASCs only at high concentrations. Taken together, these data implicate GC-TGFβ crosstalk as a determinant of depot differences in adipogenic capacity and hypertrophic vs. healthy hyperplastic expansion of AT. / 2019-11-01T00:00:00Z

yes / There are various techniques to enhance tissue regeneration via the application of growth factors to the site of regeneration to induce cells to proliferate, differentiate and regenerate. Generally, direct application of growth factors has little effect [1] because the growth factor diffuses out from the site of regeneration very quickly. This is a problem that can be solved by a controlled release of growth factor at the site of action over a long period of time by use of a bioabsorbable scaffold. Growth factors are protein based molecules in the body which are produced by cells and attach to the cell surface. Growth factors bind to membrane receptors, which in turn activate an intracellular signalling pathway. This will activate or inhibit a gene causing either an up regulation or down regulation of a gene product, which then alters the cells behaviour.

Indiana University-Purdue University Indianapolis (IUPUI) / Objective: To determine whether specific mutations within the fibroblast growth factor receptor 2 (FGFR2) gene associated with Crouzon syndrome cause a phenotype with extreme variability of expression suggesting non-penetrance in clinically normal appearing individuals. Methods: Most mutations responsible for Crouzon syndrome occur in exons IIIa(U) or IIIc(B) of the FGFR2 gene, facilitating allelotyping by using polymerase chain reaction to mediate mutation analysis. Once a specific mutation is identified in the index case, remaining affected family members and clinically normal first-degree relatives are screened in order to correlate genotype with phenotype. Results: A novel missense mutation, a G to T transversion, involving the first base of codon 362 (Ala362Ser), was identified following DNA sequencing of exon IIIc, and a specific restriction fragment length polymorphism following BstNI enzyme digestion was found in all Crouzon-affected family members and in one clinically normal-appearing parent. Pattern profile analysis demonstrated a consistent collection of abnormal cephalometric measurements in the Crouzon affected family members, and to a lesser degree, in the clinically normal parent. Conclusion: We have identified a novel missense mutation in the FGFR2 gene predicting an Ala362Ser substitution that is shared by all family members affected by Crouzon syndrome, and a clinically normal appearing father. These data support non-penetrance of Crouzon syndrome.

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