This proposal is in response to RFA-HD-09-008 Cooperative Research Partnerships to Promote Workforce Diversity in the Reproductive Sciences (U01), entitled, Kisspeptin Regulation and GPR54 Signaling in Reproduction. The application is a research partnership among Drs. Sally Radovick and Andrew Wolfe at Johns Hopkins University School of Medicine and Dr. Gloria Hoffman at Morgan State University. Undergraduate students from Morgan State University and Johns Hopkins University will be recruited and mentored under this collaborative award mechanism. The curriculum will include didactic lectures, a wide breadth of laboratory based studies and career counseling. A Steering Committee comprised of the investigators will guide the process. The release of LH is under the regulation of the neurohormone, luteinizing hormone releasing hormone (LHRH). Recently, the peptide kisspeptin (KP) that signals through a G-protein coupled receptor, GPR54, was found to be a key component in the regulation of LHRH. Evidence for a direct role for KP at the level of the LHRH neuron comes from anatomical and in vitro studies in LHRH expressing ceil lines. Two principal populations of KP neurons are described in the hypothalamus: one in the arcuate nucleus (Arc) and one in the AVPV. The AVPV KP neurons project directly to LHRH neurons and stimulate LHRH neurons at the time of an LH surge. The Arc population is not sexually dimorphic and is implicated in basal LHRH release and negative feedback in both sexes, but how it does so is unknown. While some aspects of KP regulation are preserved in primates, there is little resolution as to whether the AVPV population is present, and whether connections of the KP neurons to LHRH and other systems are preserved across species. This proposal will examine the connectivity of KP neurons with the LHRH system in rodents vs. primates and will also generate a floxed GPR54 mouse line to specifically ablate GPR54 in the LHRH neuron to study pubertal onset and estrogen feedback regulation in addition to cellular changes in LHRH neurons. In summary, this proposal will delineate both the role of KP-GPR54 signaling in estrogen feedback regulation and its locus in the central reproductive axis.

Public Health Relevance

The goal is to provide selected undergraduates the unique resources available from two institutions focused on a broad spectrum of didactic and laboratory experiences in the field of reproductive biology. Partnering to learn with academic researchers, the students will study regulatory mechanisms controlling mammalian reproduction.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project--Cooperative Agreements (U01)
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Special Emphasis Panel (ZHD1-DSR-L (08))
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Ravindranath, Neelakanta
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Johns Hopkins University
Schools of Medicine
United States
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Novaira, Horacio J; Graceli, J B; Capellino, S et al. (2016) Development and Characterization of Novel Rat Anti-mER? Sera. Endocrinology 157:2844-52
Novaira, H J; Sonko, M L; Radovick, S (2016) Kisspeptin Induces Dynamic Chromatin Modifications to Control GnRH Gene Expression. Mol Neurobiol 53:3315-3325
DiVall, Sara A; Herrera, Danny; Sklar, Bonnie et al. (2015) Insulin receptor signaling in the GnRH neuron plays a role in the abnormal GnRH pulsatility of obese female mice. PLoS One 10:e0119995
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Song, Woo-Jin; Mondal, Prosenjit; Wolfe, Andrew et al. (2014) Glucagon regulates hepatic kisspeptin to impair insulin secretion. Cell Metab 19:667-81
Wu, Sheng; Divall, Sara; Nwaopara, Amanda et al. (2014) Obesity-induced infertility and hyperandrogenism are corrected by deletion of the insulin receptor in the ovarian theca cell. Diabetes 63:1270-82
Novaira, Horacio J; Sonko, Momodou L; Hoffman, Gloria et al. (2014) Disrupted kisspeptin signaling in GnRH neurons leads to hypogonadotrophic hypogonadism. Mol Endocrinol 28:225-38
Wu, Sheng; Chen, Yi; Fajobi, Temi et al. (2014) Conditional knockout of the androgen receptor in gonadotropes reveals crucial roles for androgen in gonadotropin synthesis and surge in female mice. Mol Endocrinol 28:1670-81
Na, Giyoun; Wolfe, Andrew; Ko, Chemyong et al. (2013) A low-copy-number plasmid for retrieval of toxic genes from BACs and generation of conditional targeting constructs. Mol Biotechnol 54:504-14
Novaira, Horacio J; Fadoju, Doris; Diaczok, Daniel et al. (2012) Genetic mechanisms mediating kisspeptin regulation of GnRH gene expression. J Neurosci 32:17391-400

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