Cell type-specific endometrial dysfunctions across the menstrual cycle and their potential for drug interventions in polycystic ovary syndrome

Descripción del proyecto

Estudiar la disfunción endometrial en el síndrome de ovario poliquístico

El síndrome de ovario poliquístico (SOPQ) es un trastorno hormonal de las mujeres en edad reproductiva asociado a periodos irregulares, exceso de hormonas masculinas y ovarios con pequeños quistes. La ovulación en el SOPQ suele ser irregular y el revestimiento del útero responde menos a la progesterona. Esto reduce la implantación del embrión y aumenta el riesgo de aborto, lo que provoca problemas de fertilidad. Con el apoyo de las Acciones Marie Skłodowska-Curie, el equipo del proyecto POTRET cartografiará cómo cambian las células endometriales durante el ciclo menstrual en mujeres con SOPQ. Los investigadores desarrollarán modelos tridimensionales derivados de pacientes para estudiar la comunicación entre las células y probar nuevas dianas terapéuticas. En el proyecto se pretende mejorar el diagnóstico y los futuros tratamientos del SOPQ.

Objetivo

Polycystic ovary syndrome (PCOS) affects 11-13% of reproductive-age women and is one of the leading causes of anovulatory infertility. Women with PCOS have elevated androgen levels, polycystic ovarian morphology, and ovarian dysfunction. The PCOS endometrium is exposed to constant estrogen, which leads to progesterone resistance and impaired decidualization. As a result, PCOS women are twice as likely to have a non-receptive endometrium. This hinders embryo implantation and increases the risk of pregnancy complications, such as miscarriage. However, whether changes in the cellular complexity and heterogeneity of the endometrium during the menstrual cycle contribute to PCOS-specific endometrial dysfunction remains unclear.

The overarching aim of this MSCA-PF project is to uncover PCOS and cell type-specific endometrial dysfunction across the menstrual cycle at the single cell level and to test whether the identified markers can serve as targets for future drug development. Using a unique collection of human endometrial biopsies from women with and without PCOS and single nuclei RNA sequencing, I will (1) map the endometrium at the single-cell level at four different menstrual stages, define the composition of cell types and key molecular regulatory networks; (2) establish and characterize 3D mono- and co-culture models of patients endometrium and investigate their ability to mimic tissue of origin; and (3) determine factors that facilitate PCOS-specific epithelial-stroma communication and endometrial response to novel drug treatments.

By accomplishing these goals and sharing the transcriptomic data as a PCOS endometrial cell atlas and protocols for patient-derived cell models, the proposed project will provide valuable resources for new discoveries. Ultimately, the project aims to improve the diagnosis, treatment, and prevention of endometrial dysfunction in PCOS. Further, it provides me with a strong training path towards academic independence in Europe.