Descripción del proyecto
Información sobre el control neuroendocrino de la fertilidad
La actividad reproductora en los animales y los seres humanos se mantiene a través del eje hipotalamohipofisogonadal (HHG). El hipotálamo segrega la hormona de liberación de la gonadotrofina (GnRH), la cual regula la segregación de la hormona luteinizante (LH) y la hormona foliculoestimulante (FSH) desde la hipófisis. Se necesita tanto la LH como la FSH para estimular los ovarios y la fertilidad. El objetivo del proyecto CRISPR-KissCas9, financiado con fondos europeos, es comprender la regulación de la liberación de la GnRH pulsátil. Sus investigadores estudiarán neuropéptidos expresados por neuronas en el hipotálamo e investigarán sus funciones fisiológicas. Los resultados proporcionarán información importante sobre los mecanismos neuroendocrinos que controlan la fertilidad, sentando así las bases para mejorar los tratamientos contra la infertilidad.
Objetivo
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.
Ámbito científico
Programa(s)
Régimen de financiación
MSCA-IF-EF-RI - RI – Reintegration panelCoordinador
14005 Cordoba
España