The overall goal of this proposal is to examine the mechanism by which luteinizing hormone (LH) regulates ovarian function. LH, through its interaction with LH/hCG receptor (LHR) regulates steroid hormone production, ovulation, fertilization, implantation and pregnancy maintenance. Thus, LHR is the crucial molecule that regulates ovarian function. The major focus of the proposed studies is to determine the mechanisms modulating LHR expression in the ovary. Since LHR expression shows fluctuations during the ovarian cycle in response to a constantly changing milieu of circulating levels of LH and other factors, a relatively simple post- transcriptional mechanism to control the steady state levels of LHR would have the distinct advantage. The goal of the present study is to determine the mechanism of the post-transcriptional regulation which involves a specific LHR mRNA binding protein (LRBP).
Aim 1 will examine the signaling pathways involved in the expression of LRBP which, in turn, regulate the tissue levels of LHR mRNA. We will examine a possible role of miR122, a micro RNA, in controlling the levels of LRBP during up and downregulation of LHR mRNA using both in vivo and in vitro approaches. These studies are based on our findings that showed increased expression of miR122 during ligand-induced downregulation of LHR mRNA, and that an antagomir of mir122 blocked LRBP expression under in vivo conditions.
Aim 2 will examine the mechanism by which LRBP causes accelerated degradation of LHR mRNA under conditions that mimic the preovulatory LH surge. We propose to examine the possible participation of proteins that interact with LRBP and how these interactions culminate in blocking LHR mRNA translation, and the transport of this untranslatable complex to processing bodies for LHR mRNA degradation.
This aim i s also based on strong supporting data that identified eIF5A as an interacting partner for LRBP by yeast 2 hybrid screens as well as co-immunoprecipitation experiments.
Aim 3 will examine the functional consequences of granulosa cell-specific deletion of LRBP (mevalonate kinase) gene (cKO) on ovarian function. Proposed studies will examine the consequences of the deletion of LRBP (mevalonate kinase) gene on follicle growth, corpus luteum formation and function. Since granulosa cell- specific deletion of mevalonate kinase gene will render this tissue incapable of synthesizing cholesterol, we will also determine the compensatory elevation of cholesterol uptake from plasma lipoproteins in the ovaries from cKO animals to overcome this deficiency. The studies proposed here address novel questions that are central to reproductive endocrinology and the results might provide new insights into novel approaches for the treatment of infertility.

Public Health Relevance

Since luteinizing hormone receptor plays a central role in reproduction, the present study examining the regulation of LH receptor expression in the ovary on a molecular level is likely to make a significant impact in our understanding of the regulation of female reproductive cycle. Furthermore, the concepts derived from these studies will have relevance in the treatment of infertility.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD006656-38
Application #
8670003
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Yoshinaga, Koji
Project Start
1979-09-30
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
38
Fiscal Year
2014
Total Cost
$313,628
Indirect Cost
$111,938
Name
University of Michigan Ann Arbor
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Moravek, Molly B; Shang, Min; Menon, Bindu et al. (2016) HCG-mediated activation of mTORC1 signaling plays a crucial role in steroidogenesis in human granulosa lutein cells. Endocrine 54:217-224
Menon, Bindu; Gulappa, Thippeswamy; Menon, K M J (2015) miR-122 Regulates LH Receptor Expression by Activating Sterol Response Element Binding Protein in Rat Ovaries. Endocrinology 156:3370-80
Gulappa, Thippeswamy; Menon, Bindu; Menon, K M J (2015) Hypusination of eukaryotic initiation factor 5A via cAMP-PKA-ERK1/2 pathway is required for ligand-induced downregulation of LH receptor mRNA expression in the ovary. Mol Cell Endocrinol 413:90-5
Menon, K M J; Menon, Bindu (2014) Regulation of luteinizing hormone receptor expression by an RNA binding protein: role of ERK signaling. Indian J Med Res 140 Suppl:S112-9
Menon, Bindu; Gulappa, Thippeswamy; Menon, K M J (2014) Eukaryotic initiation factor 5A plays an essential role in luteinizing hormone receptor regulation. Mol Endocrinol 28:1796-806
Menon, Bindu; Sinden, Jennifer; Menon, K M J (2013) Association of luteinizing hormone receptor (LHR) mRNA with its binding protein leads to decapping and degradation of the mRNA in the p bodies. Biochim Biophys Acta 1833:1173-9
Menon, Bindu; Sinden, Jennifer; Franzo-Romain, Meghan et al. (2013) Regulation of LH receptor mRNA binding protein by miR-122 in rat ovaries. Endocrinology 154:4826-34
Lin, Cindy Chan Juan; Clouser, Christine; Peegel, Helle et al. (2008) The extracellular domain of luteinizing hormone receptor dictates its efficiency of maturation. Biochem Biophys Res Commun 377:307-11
Li, X; Peegel, H; Menon, K M (1998) In situ hybridization of high density lipoprotein (scavenger, type 1) receptor messenger ribonucleic acid (mRNA) during folliculogenesis and luteinization: evidence for mRNA expression and induction by human chorionic gonadotropin specifically in cell typ Endocrinology 139:3043-9
Chen, Z; Menon, K M (1994) Expression of high density lipoprotein-binding protein messenger ribonucleic acid in the rat ovary and its regulation by gonadotropin. Endocrinology 134:2360-6

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