Grants and Contracts Details
Description
Principal Investigator/Program Director (Last, First, Middle): Ko, CheMyong
DESCRIPTION: See instructions. State the application's broad, long-term objectives and specific aims, making reference to the health relatedness of
the project (i.e., relevance to the mission of the agency). Describe concisely the research design and methods for achieving these goals. Describe
the rationale and techniques you will use to pursue these goals.
In addition, in two or three sentences, describe in plain, lay language the relevance of this research to public health. If the application is funded, this
description, as is, will become public information. Therefore, do not include proprietary/confidential information. DO NOT EXCEED THE SPACE
PROVIDED.
The goal of the proposed studies is to elucidate the mechanism of endothelin-2 (EDN-2) action in follicle
rupture. The program of ovulation is activated by a surge of luteinizing hormone, which initiates dramatic
changes in molecular, biochemical, and physical aspects of the ovary, eventually leading to rupture of
follicles. However, the factors involved in and the mechanism governing the process of follicle rupture are yet
to be unveiled. Using a gene expression profiling approach, we have identified EDN-2, a potent smooth
muscle constrictor, which is exclusively and transiently expressed in the granulosa cells of periovulatory
follicles immediately prior to ovulation. We found that EDN-2 induces rapid and sustained contraction in the
ovarian tissue, while tezosentan, an endothelin receptor antagonist, released the contraction. These novel
findings led us to hypothesize that EDN-2 directly constricts periovulatory follicles leading to the rupture of
the follicle. Supporting the hypothesis, immunohistochemical analysis identified a well-organized smooth
muscle layer in the theca externa of each follicle, which forms a sponge-like smooth muscle network at the
whole ovarian level. Furthermore, we found that intraovarian injection of tezosentan prior to ovulation
completely blocked follicle rupture. In this study, we will elucidate the mechanism of EDN-2 action in follicle
rupture. We will determine the target tissues of EDN-2 action, the endothelin receptor subtype(s) that
mediates EDN-2 action, and the ovarian concentration of EDN-2. We will also determine the mechanism of
endothelin-2 induced follicular constriction in relation to other ovary-produced vasoconstrice molecules
(VIPs, PACAPs, and prostaglandins). In addition, the functional link of progesterone, estrogen, and
prostaglandin to the follicle rupture in relation to EDN-2 will be explored. The major strength of this proposal
is in the identification of EDN-2 and the ovarian smooth muscle network as the key components of follicle
rupture. The novelty of the proposed experiments is the interdisplinary approachs (genome-wide gene
expression profiling, intraovarian injection, and isometric tension measurement ). The proposed studies are
exceptionally important in order to further our understanding of the mechanism of follicle rupture. The
proposed experiments will provide clinical direction in identifying the therapeutic target for the cure of
annovulatory symptoms, one of the leading causes of female infertility.
PERFORMANCE SITE(S) (organization, city, state)
Division of Reproductive Laboratory Sciences
Department of Clinical Sciences
College of Health Sciences
University of Kentucky
900 South Limestone Street
Lexington, KY 40536
PHS 398 (Rev 09/04) Page g Form Page 2
Status | Finished |
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Effective start/end date | 5/15/06 → 2/28/12 |
Funding
- National Institute of Child Health and Human Develop: $1,171,200.00
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