Contraception and infertility are two major quality of life issues facing women of reproductive age. Ovulation of a fertilizable oocyte and formation of a functional corpus luteum are absolute requirements for reproductive success and are induced by the mid-cycle surge of luteinizing hormone (LH). Disrupted LH actions are a leading cause of infertility and a target of many contraceptive methods. Numerous studies have characterized the signaling cascades and transcriptional responses downstream of LH action;and dramatic progress in our understanding of how LH and its receptor are able to regulate such complicated physiological processes such as ovulation, resumption of meiosis and luteinization have resulted. However, significant questions still remain unsolved or unexplored, including the role post-transcriptional regulation of gene expression plays in mediating LH action. Our recent studies with Dicer1 deficient mice have implicated post-transcriptional and specifically microRNA mediated gene regulation as playing a key role in ovulation. We have also identified miR-21 as an LH- induced microRNA (miRNA) within granulosa cells of the periovulatory follicle, and demonstrated that it suppresses apoptosis and enhances granulosa cell hypertrophy by promoting global translation. Furthermore, our current in vivo studies demonstrate that loss of miR-21 decreases ovulation rate. Therefore, the central hypothesis of this proposal is that miR-21 plays critical roles in the LH-induced ovarian function. To test this central hypothesis, in Specific Aim1, we determine the function of miR-21 within periovulatory follicular granulosa cells and its role in ovulation, luteinization and oocyte competence.
In Specific Aim 2, we identify the target transcripts and molecular pathways miR-21 regulates within periovulatory granulosa cells, while in Specific Aim 3 we determine which LH-induced transcription factors modulate miR-21 gene expression. The studies proposed in this grant application will define a subset of genes regulated by miR-21 mediated post-transcriptional gene regulation and will functionally link this miRNA with physiologic and developmental events critical to ovarian function. The long-term benefits of this research will enhance our understanding of the ovary, ultimately impacting the development of treatment strategies for infertility and new contraceptive methods for women.
Infertility due to ovarian dysfunction such as polycystic ovarian syndrome, short luteal phase defects and compromised oocyte quality result from disrupted and abnormal cellular interactions occurring within the periovulatory follicle. Identifying the factors and their mechanisms of action that regulate ovarian function will provide targets for therapeutic intervention. The long-term benefits of this research will enhance our understanding of the ovary, ultimately impacting the development of treatment strategies that will improve the reproductive health of women.
|Pohler, Ky G; Green, Jonathan A; Moley, Laura A et al. (2017) Circulating microRNA as candidates for early embryonic viability in cattle. Mol Reprod Dev 84:731-743|
|Fitzgerald, J Browning; George, Jitu; Christenson, Lane K (2016) Non-coding RNA in Ovarian Development and Disease. Adv Exp Med Biol 886:79-93|
|Navakanitworakul, Raphatphorn; Hung, Wei-Ting; Gunewardena, Sumedha et al. (2016) Characterization and Small RNA Content of Extracellular Vesicles in Follicular Fluid of Developing Bovine Antral Follicles. Sci Rep 6:25486|
|Hung, Wei-Ting; Hong, Xioman; Christenson, Lane K et al. (2015) Extracellular Vesicles from Bovine Follicular Fluid Support Cumulus Expansion. Biol Reprod 93:117|
|McGinnis, Lynda K; Luense, Lacey J; Christenson, Lane K (2015) MicroRNA in Ovarian Biology and Disease. Cold Spring Harb Perspect Med 5:a022962|
|Burns, Gregory; Brooks, Kelsey; Wildung, Mark et al. (2014) Extracellular vesicles in luminal fluid of the ovine uterus. PLoS One 9:e90913|
|Gawriluk, Thomas R; Ko, CheMyong; Hong, Xiaoman et al. (2014) Beclin-1 deficiency in the murine ovary results in the reduction of progesterone production to promote preterm labor. Proc Natl Acad Sci U S A 111:E4194-203|
|Elsarraj, Hanan S; Hong, Yan; Valdez, Kelli et al. (2013) A novel role of microRNA146b in promoting mammary alveolar progenitor cell maintenance. J Cell Sci 126:2446-58|
|Christenson, Lane K; Gunewardena, Sumedha; Hong, Xiaoman et al. (2013) Research resource: preovulatory LH surge effects on follicular theca and granulosa transcriptomes. Mol Endocrinol 27:1153-71|
|Veiga-Lopez, Almudena; Luense, Lacey J; Christenson, Lane K et al. (2013) Developmental programming: gestational bisphenol-A treatment alters trajectory of fetal ovarian gene expression. Endocrinology 154:1873-84|
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