The overall objective of this proposal is to examine the molecular mechanism(s) involved in the regulation of ovarian function by leuteinizing hormone (LH). The initial event is the interaction of LH with a specific receptor on the ovarian cell surface. Through this interaction with a specific cell surface receptor LH regulates ovarian follicular development, ovulation and corpus luteum function. By these means LH regulates fertility, implantation and early pregnancy. The present study focuses on the regulation of the expression of LH receptor on the cell surface. Specifically, the first specific aim examines the mechanism by which the steady state levels of LH receptor are regulated during follicle maturation and during the peri-ovulatory periods. The specific studies oroposedto examine this aim will elucidate the role of a newly identified protein, LH receptor mRNA binding protein, in the post- transcriptional regulation of LH receptor mRNA. These studies will determine the mechanism by which LH receptor mRNA is degraded by LH receptor mRNA binding protein. The specific studies proposed will also make use of an in vitro LH receptor mRNA decay assay to examine the LH receptor mRNA degradation rates, aid an electrophoretic mobility gel shift assay to examine the LH receptor mRNA binding activity of the binding protein. The second specific aim will determine the role of post-translational modification on the turnover of LH receptor on the cell surface, Specifically, this aim will address the role of palimitoylation/depalmitoylation of LH receptor on receptor turnover after interaction with LH.
This aim will also address the mechanism(s) involved in the arrestin-mediated internalization of the LH-bound receptor. The studies will utilize among other techniques, pulse labeling of epitope- tagged LH receptor and immunoprecipitation of the labeled receptor. The third specific aim will address the role of post-translational modification of the LH receptor on its folding and cell surface expression. The proposed experiments in specific aim 3 would involve mutation of the consensus glycosylation sites of the LH receptor and transfection of the receptor constructs to examine the role of glycosylation on folding and cell surface expression. These studies address novel questions central to reproductive endocrinology and are directly relevant to the diagnosis and treatment of infertility.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HD006656-35
Application #
7806417
Study Section
Special Emphasis Panel (NSS)
Program Officer
Yoshinaga, Koji
Project Start
1979-09-30
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
35
Fiscal Year
2010
Total Cost
$291,992
Indirect Cost
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, 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; 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, K M J; Menon, Bindu (2012) Structure, function and regulation of gonadotropin receptors - a perspective. Mol Cell Endocrinol 356:88-97
Gulappa, Thippeswamy; Clouser, Christine L; Menon, K M J (2011) The role of Rab5a GTPase in endocytosis and post-endocytic trafficking of the hCG-human luteinizing hormone receptor complex. Cell Mol Life Sci 68:2785-95
Menon, Bindu; Franzo-Romain, Megan; Damanpour, Shadi et al. (2011) Luteinizing hormone receptor mRNA down-regulation is mediated through ERK-dependent induction of RNA binding protein. Mol Endocrinol 25:282-90
Wang, Lei; Gulappa, Thippeswamy; Menon, K M J (2010) Identification and characterization of proteins that selectively interact with the LHR mRNA binding protein (LRBP) in rat ovaries. Biochim Biophys Acta 1803:591-7
Harada, M; Peegel, H; Menon, K M J (2010) Expression of vascular endothelial growth factor A during ligand-induced down-regulation of luteinizing hormone receptor in the ovary. Mol Cell Endocrinol 328:28-33
Menon, K M J; Menon, B; Wang, L et al. (2010) Molecular regulation of gonadotropin receptor expression: relationship to sterol metabolism. Mol Cell Endocrinol 329:26-32
Shah, Divya K; Menon, K M J; Cabrera, Lourdes M et al. (2010) Thiazolidinediones decrease vascular endothelial growth factor (VEGF) production by human luteinized granulosa cells in vitro. Fertil Steril 93:2042-7

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