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.
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.
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|Kawate, N; Menon, K M (1994) Palmitoylation of luteinizing hormone/human choriogonadotropin receptors in transfected cells. Abolition of palmitoylation by mutation of Cys-621 and Cys-622 residues in the cytoplasmic tail increases ligand-induced internalization of the receptor. J Biol Chem 269:30651-8|
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|Chen, Z; Menon, K M (1993) Identification of a scavenger receptor in rat luteal cells which recognizes chemically modified lipoproteins and mediates the uptake of cholesterol for steroidogenesis. Biochim Biophys Acta 1150:79-88|
|Ferreri, K; Talavera, F; Menon, K M (1992) Increased cellular cholesterol upregulates high density lipoprotein binding to rat luteal cells. Endocrinology 131:2059-64|
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