Project 3 - Brayboy

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ABSTRACT/SUMMARY The US birth rate has fallen over the past 30 years while births from women ages 35-55 instead have increased. Advanced maternal age in pregnancy carries a higher risk of gestational hypertension/preeclampsia (OR 2.42), and gestational diabetes (OR 1.11). Pregnancy has long been regarded as a “stress test” which may herald the development of overt diseases in older women who are predisposed, or have already developed subclinical pathophysiology. Older women who require treatment with in vitro fertilization have an even higher risk of developing these obstetric complications even when controlling statistically for age. This highlights that an additional insult may be initiated by superovulation or perhaps embryo culture. Unfortunately, physicians have no mechanistic understanding of why this is the case, or how to predict the outcome more effectively. However, recent studies have examined the transcriptomic profile of cumulus cells to reveal pathophysiology in the mother. Further, the cumulus cell transcriptome is different in young and aged patients undergoing IVF. The findings report that women >37 years old showed over expression of angiogenic genes by the cumulus cells, including ANGPTL4 (angiopoietin like 4), LEPR (leptin receptor), TGFBR3 (transforming growth factor beta receptor III), and FGF2 (fibroblast growth factor). Even patients 31- 36 years of age overexpressed genes related to the insulin signaling pathway such as IGFBP3 (insulin like growth binding factor 3), P1K3R1 (Phosphoinositide-3-Kinase, Regulatory Subunit 1 (Alpha)), and IGFBP5 (Insulin-Like Growth Factor Binding Protein 5), suggesting a transition to pregnancy-related diabetes. We hypothesize that overexpression of these genes and others responsive to a two-hit model of maternal stress, could be predictive for the increased rates of gestational diabetes and hypertension manifested in older parturients. However, no study to date has followed patients longitudinally to determine if altered cumulus cell gene expression is clinically relevant. Our objective is to determine how effective these metrics in the cumulus cells are in aged humans in predicting disease manifestation. To address this we propose the following specific aims: Specific Aim 1: Correlate candidate transcripts involved in angiogenesis (ANGPTL4, LEPR, TGFBR3, and FGF2), of the insulin pathway (IGFBP3, P1K3R1 and IGFBP5), and of general transcript profiles with pregnancy complications in aged women undergoing IVF; Specific Aim 2: Determine how significantly mice have altered gene expression in their cumulus cells during aging and how these profiles may reflect aged women undergoing IVF. Specific Aim 3: Retrospective associations will be conducted on patients in Aim 1 with the molecular profiles acquired from their cumulus cells.