The Kissi gene encodes proteins called kisspeptins, v^rhich bind to the G-protein coupled receptor GPR54. Kissl is expressed in discrete brain regions that regulate reproductioa and in mammals, induding humans, kisspeptins stimulate the secretion of gonadotropin-releasing hormone (GnRH) and gonadotropins (LH, FSH). Kissl neurons are themselves regulated by gonadal sex hormones, suggesting a crucial role for kisspeptin signaling in the negative and positive feedback regulation of reproduction. Although the stimulatory role of kisspeptin-GPR54 signaling in the control of GnRH secretion has been well-studied, the role of Kissl nemons in the environmental, circadian, and developmental regulation of reproductioivis much less cftaractenzea. ine goals or this research are to elucidate the physiological role Ofthe KiHlil system in the circadian, photoperiodic, and developmental control of GnRH secretion. The first objective is to evaluate the role of Kissl neurons in the drcadian-controlled pre-ovulatory LH surge. In females, the pre-ovulatory LH surge is coupled to a circadian oscillator in the suprachiasmatic nucleus (SCN). Althoiigh the rieural circuitry and neuroendocrine factors that mediate the SCN's control of the surge remain unidentified, evidence implicates the involvement of Kissl neurons. I will investigate whether Kissl neurons undergo circadian activation at the time of daily LH surges and determine whether there are direct neural cormections between the SCN and Kissl neurons (and if so, identify" the neurotransmitters involved in this circuitry). The second main objective is to evaluate the role of Kissl neurons in the seasonal control of reproduction and sexual maturation. It is known that seasoital reproduction and puberty onset are governed by pineal melatonin (MEL) secretion (which reflects day length), but the neural circuitry that integrates and relays MEL signals to GnRH neurons remains unidentified. I wiU assess the effects of photoperiod/MEL on the hypothalamic Kissl system, ascertain whether MEL's effects on Kissl neurons are direct or indirect, and determine how the regulation of Kissl neurons varies with developmental status (puberty). I will also comprehensively evaluate the roles of several candidate nuclei in relaying any indirect effects of MEL on Kissl neurons. Lastly, I will investigate how the irmervatipn of GnRH neurons by Kissl axons and the sensitivity oi Kissl neurons to feedback effects of sex steroids areregulated by photoperiod and developmental status.

Public Health Relevance

Elucidating the role of Kissl neurons in the regulation of GnRH secretion in mammals could offer further insight into the neural and endocrine mechanisms responsible for idiopathic hypogonadotropic hypogonadism in humans and could provide the sdentific rationale for potential new therapies to treat precocious or delayed puberty, menstrual cyde irregularities, infertility, and other reproductive and sexual disorders.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Transition Award (R00)
Project #
5R00HD056157-05
Application #
8009415
Study Section
Special Emphasis Panel (NSS)
Program Officer
Lamar, Charisee A
Project Start
2007-09-01
Project End
2012-03-31
Budget Start
2011-01-01
Budget End
2012-03-31
Support Year
5
Fiscal Year
2011
Total Cost
$240,079
Indirect Cost
Name
University of California San Diego
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Kauffman, Alexander S; Thackray, Varykina G; Ryan, Genevieve E et al. (2015) A Novel Letrozole Model Recapitulates Both the Reproductive and Metabolic Phenotypes of Polycystic Ovary Syndrome in Female Mice. Biol Reprod 93:69
Khan, A R; Kauffman, A S (2012) The role of kisspeptin and RFamide-related peptide-3 neurones in the circadian-timed preovulatory luteinising hormone surge. J Neuroendocrinol 24:131-43
Poling, Matthew C; Kauffman, Alexander S (2012) Sexually dimorphic testosterone secretion in prenatal and neonatal mice is independent of kisspeptin-Kiss1r and GnRH signaling. Endocrinology 153:782-93
Kim, Joshua; Semaan, Sheila J; Clifton, Donald K et al. (2011) Regulation of Kiss1 expression by sex steroids in the amygdala of the rat and mouse. Endocrinology 152:2020-30
Semaan, Sheila J; Kauffman, Alexander S (2010) Sexual differentiation and development of forebrain reproductive circuits. Curr Opin Neurobiol 20:424-31
Semaan, Sheila J; Murray, Elaine K; Poling, Matthew C et al. (2010) BAX-dependent and BAX-independent regulation of Kiss1 neuron development in mice. Endocrinology 151:5807-17
Kauffman, Alexander S; Bojkowska, Karolina; Rissman, Emilie F (2010) Critical periods of susceptibility to short-term energy challenge during pregnancy: Impact on fertility and offspring development. Physiol Behav 99:100-8
Kauffman, A S (2010) Gonadal and nongonadal regulation of sex differences in hypothalamic Kiss1 neurones. J Neuroendocrinol 22:682-91
Kauffman, Alexander S (2010) Coming of age in the kisspeptin era: sex differences, development, and puberty. Mol Cell Endocrinol 324:51-63
Kauffman, Alexander S; Navarro, Victor M; Kim, Joshua et al. (2009) Sex Differences in the Regulation of Kiss1/NKB Neurons in Juvenile Mice: Implications for the Timing of Puberty. Am J Physiol Endocrinol Metab :

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