The primary objective of this proposal is to facilitate the development of Dr. Alvarez into an independent research scientist. This objective will be accomplished through a combination of active mentorship, didactic training, enrichment activities, and research. The mentorship phase is well described by his mentor and includes weekly contact and formal course work. The core of the research focuses on the effects of aging on a post-transcriptional regulation mechanism known as RNA editing on fertility and oocyte quality. Maternal age represents a significant confounding factor associated with decreased fertility. The contribution of RNA post- transcriptional regulation such as RNA editing to age related fertility is unknown. Central to RNA editing is the family of adenosine deaminases acting on double stranded RNA (ADARs), that catalyze the deamination of an adenosine (A), generating an inosine (I) in regions of double stranded RNA (dsRNA). The goal of this research is to determine the effect maternal age has on RNA editing and RNA stability in the oocyte. Our preliminary data show that ADAR1 expression and RNA editing are attenuated in reproductively aged mice and humans, respectively. We hypothesize that ADAR1 deficiency could be involved in female age- associated decline of fertility. Specifically, we predict that ADAR1 RNA editing is required for female fertility through the regulation of RNA stability during oocyte growth and early embryonic development. The hypothesis will be tested in two independent specific aims.
Specific Aim 1 will identify the effects of A-to-I editing on transcriptional networks in reproductively young and old human oocytes and eggs.
Specific Aim 2 will examine how ADAR1 A-to-I 3? UTR RNA editing effects RNA stability and oocyte quality in reproductively young and old mice. Completion of these studies will expand our knowledge of how post- transcriptional regulatory events contribute to oocyte quality and fertility, and will enable Dr. Alvarez to achieve independence as a research scientist.
Aging in women is associated with a decline in fertility. In this proposal we will examine how aging alters RNA editing in oocytes and how RNA editing alters transcriptional networks necessary for maintaining oocyte quality. This research will lead to a better understanding of oocyte specific post-transcriptional regulatory mechanisms during the process of age related fertility decline in women.