# Sex Steroids, Kisspeptin and Regulation of GnRH

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2024 · $448,282

## Abstract

Project Summary
 The central nervous system regulates gonadotropin secretion through neurosecretion of gonadotropin-
releasing hormone (GnRH). GnRH is synthesized in preoptic and periventricular neurons, transported via
intertwined processes that distribute as axonal-vascular terminals in the median eminence and released into the
hypothalamic-hypophysial portal vasculature. GnRH binds receptors on gonadotropes to stimulate secretion and
synthesis of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Neurosecretion of GnRH is
pulsatile and is obligatory for sustaining normal gonadotropin secretion and synthesis.
 Kisspeptin (KISS1) neurons are a major GnRH afferent network that activates GnRH neurons during
puberty, maintains GnRH release during adulthood, and transduces negative and positive feedback actions of
gonadal steroids. In our studies we will test the hypothesis that KISS1 neurons, specifically those in the arcuate
nucleus (ARC) that co-express the peptides neurokinin B (NKB) and prodynorphin (PDyn) (KNDy neurons),
function as a GnRH pulse generator (Aim 1), with NKB mediating synchronized activation of KNDy cells (Aim 2)
and dynorphin terminating each pulse discharge (Aim 3). These studies are significant because they will provide
information on the cellular circuitries that govern GnRH pulse generation, and thus will shed new light on the
pathophysiologic mechanisms underlying neuroendocrine-based fertility disorders, such as absent, delayed, or
precocious puberty, functional hypothalamic amenorrhea, or polycystic ovary syndrome, and in the longer term,
point to new potential targets for intervention in these reproductive impairments.
 The proposed studies will use powerful genetic tools to dissect and characterize the functional
components of the kisspeptin-GnRH pulse generating system. To define the key elements of the pulse generator,
we will utilize innovative genetically modified mouse models, each enabling an analysis of the consequences of
kisspeptin neuron-specific gene deletion. We will first study the role of the KNDy neuronal population using a
Kiss1fl/fl mouse recently created in our laboratory. This mouse will be bred to a prodynorphin Cre (Pdyn-IRES-
Cre21,2) mouse, hereafter Pdyn-Cre, to eliminate Kiss1 in KNDy neurons. We have also developed a novel
mouse bearing a doxycycline-inducible kisspeptin-Cre allele (iKiss-Cre mouse) that will enable temporal control
over the selective deletion of genes from Kiss1 neurons. Two other lines, a NKBfl/fl mouse (developed in our
laboratory) and an Oprk1fl/fl mouse (Jackson labs) will be crossed to Kiss1-Cre or iKiss-Cre mice to generate
mice that will allow us to analyze the effects of kisspeptin neuron-specific deletion of NKB and Oprk1 on GnRH-
triggered LH pulses. We will also use the iKiss-Cre mouse to delete and study the roles of steroid receptors in
kisspeptin neurons in the adult. This temporally controlled gene deletion will eliminate a longstanding technical
...

## Key facts

- **NIH application ID:** 11088959
- **Project number:** 7R01HD102169-05
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Jon E Levine
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $448,282
- **Award type:** 7
- **Project period:** 2020-06-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11088959

## Citation

> US National Institutes of Health, RePORTER application 11088959, Sex Steroids, Kisspeptin and Regulation of GnRH (7R01HD102169-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/11088959. Licensed CC0.

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