Projektbeschreibung
Einblicke in die neuroendokrine Regulierung der Fruchtbarkeit
Die Fortpflanzungsaktivität von Tieren und Menschen wird durch die Hypothalamus-Hypophysen-Gonaden-Achse aufrechterhalten. Der Hypothalamus sondert das Gonadotropin-Releasing-Hormon (GnRH) ab, welches die Ausschüttung des luteinisierenden Hormons und des follikelstimulierenden Hormons aus der Hypophyse reguliert. Beide Hormone sind für die Stimulation der Eierstöcke und die Fruchtbarkeit erforderlich. Im EU-finanzierten Projekt CRISPR-KissCas9 soll nun die Steuerung der pulsweisen GnRH-Freisetzung erforscht werden. Die Forschenden konzentrieren sich auf bestimmte Neuropeptide, die durch neuronale Zellen im Hypothalamus exprimiert werden, und untersuchen deren physiologischen Funktionen. Die Ergebnisse werden wichtige Informationen zum neuroendokrinen Mechanismus liefern, der die Fruchtbarkeit reguliert. Das legt die Grundlage für bessere Behandlungen von Unfruchtbarkeit.
Ziel
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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MSCA-IF-EF-RI - RI – Reintegration panelKoordinator
14005 Cordoba
Spanien