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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD061580-04
Application #
8475357
Study Section
Cellular, Molecular and Integrative Reproduction Study Section (CMIR)
Program Officer
Taymans, Susan
Project Start
2010-06-01
Project End
2015-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
4
Fiscal Year
2013
Total Cost
$289,583
Indirect Cost
$81,916
Name
University of Kansas
Department
Physiology
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
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
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