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Challenging the KNDy Hypothesis Using CRISPR-Cas9 Genome Editing: Evaluation of the Role of Neurokinin B and Dynorphin in Kiss1 neurons in the Control of Fertility

Project description

Insight into neuroendocrine control of fertility

Reproductive activity in animals and humans is maintained by the hypothalamic–pituitary–gonadal (HPG) axis. The hypothalamus secretes gonadotropin-releasing hormone (GnRH), which regulates secretion of luteinising hormone (LH) and follicle-stimulating hormone (FSH) from the pituitary gland. Both LH and FSH are necessary for ovary stimulation and fertility. The scope of the EU-funded CRISPR-KissCas9 project is to understand the regulation of pulsatile GnRH release. Researchers will focus on specific neuropeptides expressed by neuronal cells in the hypothalamus and investigate their physiological roles. Results will provide important information on the neuroendocrine mechanisms that control fertility, laying the foundation for improved treatments against infertility.

Objective

The function of the hypothalamic-pituitary-gonadal (HPG) axis is mastered by the hypothalamic neuronal population producing gonadotropin-releasing hormone (GnRH), which regulates LH and FSH secretion by the pituitary. Perturbations of fertility, e.g. in polycystic ovarian syndrome (PCOS) and hypogonadism associated with metabolic disorders, are related to functional alterations in the neuronal networks controlling pulsatile GnRH secretion. Recently, a neuronal population in the hypothalamic arcuate nucleus (ARC), which synthesizes kisspeptins (Kp; products of the Kiss1 gene), has been identified as an essential element in the regulation of pulsatile GnRH release. This ARC Kiss1 neuronal population co-expresses the neuropeptides, neurokinin B (NKB; encoded by Tac2) and dynorphin-A (Dyn; encoded by Pdyn); the term KNDy (for Kiss1, NKB & Dyn) has been coined to name this population. Different studies have pointed out the reciprocal stimulatory and inhibitory roles of NKB and Dyn, respectively, in the control of Kp output, which seemingly play a crucial role in the control of GnRH pulse generation. However, the relevance of such NKB/Dyn interplay in the dynamic control of GnRH release in different (patho)-physiological conditions, and whether this is fully dependent on Kp signaling, has not been fully clarified. We propose here to apply for the first time somatic genome editing of Tac2, Pdyn and Kiss1 loci in KNDy neurons, by using the CRISPR/Cas9 technology and virogenetic tools in suitable genetic mouse models, to address the physiological roles of NKB and Dyn in the dynamic control of GnRH neurosecretion, and their dependence on Kp signaling. The studies outlined in this proposal will substantially advance our understanding of basic neuroendocrine mechanisms for the control of fertility and will aid for the development of better strategies to treat reproductive abnormalities, such as polycystic ovarian syndrome and in/ subfertility related to metabolic disorders.

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Coordinator

UNIVERSIDAD DE CORDOBA
Net EU contribution
€ 160 932,48
Address
Avenida de medina azahara 5
14005 Cordoba
Spain

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Region
Sur Andalucía Córdoba
Activity type
Higher or Secondary Education Establishments
Links
Other funding
€ 0,00