In response to the preovulatory LH surge, the preovulatory follicle rapidly increases progesterone production, which is essential for ovulation and/or corpus luteum formation. Although this rise in progesterone level has been mainly linked to a few LH-induced genes involved in steroidogenesis (e.g., StAR, Cypi 1 a l , and HSD3b), but there are many gaps in our understanding of periovulatory accumulation of progesterone. In this proposal, we put forward a novel protein, CIPAR1 (castration-induced prostatic apoptosis-related protein 1), as a vital mediator of progesterone accumulation in the periovulatory follicle. We have recently demonstrated the LH surge increases the expression of Ciparl in periovulatory follicles of rodent ovaries. More importantly, our preliminary study using granulosa cell cultures showed that knockdown of Ciparl expression resulted in significant reduction of progesterone levels. Based on these novel findings, we hypothesize that induction of CIPAR1 by the LH surge is crucial for progesterone accumulation in periovulatory follicles, thus ovulation and luteinization.
In specific Aim#1, we will demonstrate that the alteration of Ciparl expression by silencing or over-expression affects progesterone production in rat periovulatory follicles using both in vivo and in vitro models. As the first approach to pinpoint the functional contribution of C1PAR1 in periovulatory follicles, we will identify the genes and proteins that are differentially expressed when Ciparl expression is silenced or over-expressed in periovulatory follicles. Because littie is known about cellular function of CIPAR1, Specific Aim #2 focuses on first determining the cellular location of CIPAR1 in periovulatory granulosa cells using confocal co-localization and/or subcellular fractionated protein analyses and then identifying CIPAR1 interacting proteins in periovulatory granulosa cells using immunoprecipitation, followed by a proteomic approach. Other than our preliminary data detecting Ciparl expression in human granulosa cells, nothing is known about CIPAR1 in human tissues. In collaboration with Drs. Brannstrum and Duffy, specific Aim #3 will determine whether Ciparl expression is hormonally regulated during the periovulatory period and critical for LH-induced progesterone production in humans and/or macaques. Data obtain from the proposed studies will unravel the role of C1PAR1 as a novel and critical mediator of progesterone accumulation in periovulatory follicles of primates as well as rodents.

Public Health Relevance

Progesterone plays a vital role in many aspects of reproduction, including ovulation and corpus function, therefore female fertility. Identifying the cellular function of CIPAR1 will improve our understanding of mechanisms controlling progesterone production and may suggest a novel target for managing female fertility.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
1P01HD071875-01A1
Application #
8609430
Study Section
Special Emphasis Panel (ZHD1-DRG-D (41))
Project Start
Project End
Budget Start
2014-09-19
Budget End
2015-06-30
Support Year
1
Fiscal Year
2014
Total Cost
$168,269
Indirect Cost
$56,090
Name
University of Kentucky
Department
Type
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40506
Lee-Thacker, Somang; Choi, Yohan; Taniuchi, Ichiro et al. (2018) Core Binding Factor ? Expression in Ovarian Granulosa Cells Is Essential for Female Fertility. Endocrinology 159:2094-2109
Hannon, Patrick R; Duffy, Diane M; Rosewell, Katherine L et al. (2018) Ovulatory Induction of SCG2 in Human, Nonhuman Primate, and Rodent Granulosa Cells Stimulates Ovarian Angiogenesis. Endocrinology 159:2447-2458
Bender, Hannah R; Trau, Heidi A; Duffy, Diane M (2018) Placental Growth Factor Is Required for Ovulation, Luteinization, and Angiogenesis in Primate Ovulatory Follicles. Endocrinology 159:710-722
Choi, Yohan; Rosewell, Katherine L; Brännström, Mats et al. (2018) FOS, a Critical Downstream Mediator of PGR and EGF Signaling Necessary for Ovulatory Prostaglandins in the Human Ovary. J Clin Endocrinol Metab 103:4241-4252
Park, Chan Jin; Chen, Guanglin; Koo, Yongbum et al. (2017) Generation and characterization of an estrogen receptor alpha-iCre knock-in mouse. Genesis 55:
Li, Fei-Xue; Yu, Jiao-Jiao; Liu, Ying et al. (2017) Induction of Ectonucleotide Pyrophosphatase/Phosphodiesterase 3 During the Periovulatory Period in the Rat Ovary. Reprod Sci 24:1033-1040
Puttabyatappa, Muraly; Al-Alem, Linah F; Zakerkish, Farnosh et al. (2017) Induction of Tissue Factor Pathway Inhibitor 2 by hCG Regulates Periovulatory Gene Expression and Plasmin Activity. Endocrinology 158:109-120
Choi, Yohan; Park, Ji Yeon; Wilson, Kalin et al. (2017) The expression of CXCR4 is induced by the luteinizing hormone surge and mediated by progesterone receptors in human preovulatory granulosa cells. Biol Reprod 96:1256-1266
Choi, Yohan; Wilson, Kalin; Hannon, Patrick R et al. (2017) Coordinated Regulation Among Progesterone, Prostaglandins, and EGF-Like Factors in Human Ovulatory Follicles. J Clin Endocrinol Metab 102:1971-1982
Kim, Soon Ok; Trau, Heidi A; Duffy, Diane M (2017) Vascular endothelial growth factors C and D may promote angiogenesis in the primate ovulatory follicle. Biol Reprod 96:389-400

Showing the most recent 10 out of 28 publications