ENDOTHELIN-2 IN OVARIAN FOLLICLE RUPTURE
Chemyong Ko, Associate Professor
University Of Kentucky, 109 Kinkead Hall, Lexington, Ky 40506-0057
Grant 5R01HD052694-05 from Eunice Kennedy Shriver National Institute Of Child Health & Human Development
Keywords: 1-(4-chlorobenzoyl)-5-methoxy- 2-methyl-1-H-indole-3-acetic acid; 1H-Indole-3-acetic acid, 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-; 5-isopropyl-pyridine-2-sulfonic acid 6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-1H-tetrazol-5-yl--pyridin-4-yl)--pyrimidin-4-ylamide; Animal Model; Animal Models and Related Studies; Binding Sites; Biochemical; Biochemical Process; Body Tissues; COX-2; COX2; Cannot achieve a pregnancy; Cell/Tissue, Immunohistochemistry; Clinical; Combining Site; Common Rat Strains; Corpus Luteum; Corpus Luteum Hormone; Cyst; Data Banks; Data Bases; Databank, Electronic; Databanks; Database, Electronic; Databases; Delta4-pregnene-3, 20-dione; Development; Difficulty conceiving; Disease; Disorder; EDN2; ERalpha; ET-2; Endothelin; Endothelin Receptor; Endothelin Receptor Antagonist; Endothelin-2; Endothelium-Derived Vasoconstrictor Factors; Estradiol Receptor alpha; Estrogen Receptor alpha; Estrogenic Agents; Estrogenic Compounds; Estrogens; Experimental Models; Experimental Models, Other; Expression Profiling; Expression Signature; Externa, Theca; FLR; Failure (biologic function); Fallopian Tubes; Female infertility; Gene Expression; Gene Expression Monitoring; Gene Expression Pattern Analysis; Gene Expression Profiling; Generalized Growth; Genes; Genetics, in situ Hybridization; Genital System, Female, Ovary; Goals; Growth; His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn; Hormonal; IHC; Immunohistochemistry; Immunohistochemistry Staining Method; Immunologic, Radioimmunoassay; In Situ Hybridization; Individual; Indocin; Indometacin; Indomethacin; Infertility; Injection of therapeutic agent; Injections; Interstitial Cell Stimulating Hormone; Interstitial Cell-Stimulating Hormone; Investigators; Isometric Exercise; Isometrics; Knockout Mice; Knowledge; Label; Lead; Leuteinizing Hormone; Link; Luteinizing Hormone; Lutropin; Mammalian Oviducts; Mammals, Mice; Mammals, Rats; Measurement; Measures; Mediating; Methods and Techniques; Methods, Other; Mice; Mice, Knock-out; Mice, Knockout; Models, Experimental; Molecular; Molecular Fingerprinting; Molecular Profiling; Murine; Mus; Muscle, Involuntary; Muscle, Smooth; Muscle-Setting Exercise; Null Mouse; Oocytes; Ovarian; Ovarian Diseases; Ovarian Disorder; Ovarian Follicle; Ovarian Tissue; Ovary; Ovocytes; Ovulation; PGG/HS; PGHS-2; PHM27; PHS-2; PTGS2; PTGS2 gene; Pattern; Pb element; Pituitary Gonadotropins; Pituitary Lutenizing Hormone; Porifera; Pregn-4-ene-3, 20-dione; Pregnenedione; Process; Profilings, Gene Expression; Progesterone; Progesterone Receptors; Programs (PT); Programs [Publication Type]; Prostaglandins; Prostanoids; R 38486; R38486; RIA; RT-PCR; RTPCR; RU-38486; RU-486; RU38486; RU486; Radioimmunoassay; Rat; Rattus; Reactive Site; Receptor Protein; Receptors, Endothelium-Derived Vasoconstrictor Factor; Receptors, Progesterone; Receptors, Progestin; Recombinant Luteinizing Hormone; Research Personnel; Researchers; Residual; Residual state; Reverse Transcriptase Polymerase Chain Reaction; Role; Rupture; Salpinx; Smooth muscle (tissue); Sponges; Sponges (Zoology); Static Exercise; Structure of corpus luteum of ovary; Symptoms; Syndrome; System; System, LOINC Axis 4; Techniques; Theca Externa; Therapeutic Estrogen; Therapeutic LH; Therapeutic Progesterone; Tissue Growth; Tissues; Transcript Expression Analyses; Transcript Expression Analysis; Uterine Tubes; VIP; Vasoactive Intestinal Peptide; Vasoactive Intestinal Polypeptide; Vasointestinal Peptide; clinical data repository; clinical data warehouse; constriction; corpus luteum; data repository; disease/disorder; experiment; experimental research; experimental study; failure; genome-wide; granulosa cell; hCOX-2; heavy metal Pb; heavy metal lead; in situ Hybridization Staining Method; in vivo; infertile; inhibitor; inhibitor/antagonist; intraovarian; model organism; molecuar profile; molecular signature; muscular structure; muscular system; novel; ontogeny; ovary disorder; oviduct; progesterone receptor; programs; receptor; relational database; research study; reverse transcriptase PCR; social role; tezosentan; therapeutic development; therapeutic target; unable to bear children
Project start date: 2006-05-15
Project end date: 2011-02-28
Budget start date: 1-MAR-2010
Budget end date: 28-FEB-2011
5R01HD052694-05 (2010): $229100
Sponsored Links Excellgen http://Excellgen.com
Endothelin-2 In Ovarian Follicle Rupture
Chemyong Ko
University Of Kentucky 109 Kinkead Hall Lexington, Ky 405060057
Grant 5R01HD052694-02 from National Institute Of Child Health And Human Development IRG: CMIR
Abstract: 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 vasoconstrictive 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 interdisciplinary approaches (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.
Keywords: endothelin, injury, Porifera, binding site, egg /ovum, estrogen, estrogen receptor, fallopian tube, female, fertility, gene, gene expression, gene expression profiling, genetically modified animal, genome, gonadotropin, granulosa cell, immunocytochemistry, in situ hybridization, indomethacin, information system, laboratory mouse, lead, luteinizing hormone, measurement, model, muscle, ovary, ovary disorder, ovulation, peptide, progesterone, progesterone receptor, prostaglandin, radioimmunoassay, receptor, role, smooth muscle, success, syndrome, tissue
Project start date: 2006-05-15
Project end date: 2011-02-28
5R01HD052694-02 (2007): $236137
Grants awarded to Chemyong Ko
Endothelin-2 In Ovarian Follicle Rupture
Chemyong Ko
University Of Kentucky 109 Kinkead Hall Lexington, Ky 405060057
Grant 1R01HD052694-01 from National Institute Of Child Health And Human Development IRG: CMIR
Abstract: 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 vasoconstrictive 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 interdisciplinary approaches (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.
Keywords: corpus luteum, disease /disorder etiology, endothelin, female reproductive system disorder, hormone regulation /control mechanism, ovulation, binding site, estrogen receptor, hormone metabolism, hormone receptor, muscle contraction, peptide, progesterone receptor, prostaglandin, protein structure function, receptor expression, smooth muscle, autoradiography, genetically modified animal, immature animal, immunocytochemistry, in situ hybridization, laboratory mouse, laboratory rat, mature animal, radioimmunoassay
Project start date: 2006-05-15
Project end date: 2011-02-28
1R01HD052694-01 (2006): $243135