Ricerca Progetti nazionali, regionali, internazionaliNAZIONALIPRIN 2022Identification of novel molecular mechanisms

Identification of novel molecular mechanisms affecting spermatogenesis, sperm maturation and epigenetic signature in obesity-related male infertility

Extracellular vesicles (EVs) are important effectors in cell-to-cell communication. Their cargo - including RNAs, lipids and proteins - is also provided to spermatozoa (SPZ) during their maturation, thus conferring them a new molecular guise. Obesity is an alarming health concern of modern society reaching epidemic dimensions. It is associated with an increased prevalence of male infertility, linked to a deregulated apoptosis of testicular germ cells, related to endoplasmic reticulum (ER) stress and, therefore, responsible for the alteration in sperm protein content. This affects sperm maturation and fertilization. To address this societal need an urgent development of innovative cell-based strategies is required, with a coordinated multi-tasking approach that investigates the role of EVs, which may supply novel insights into the mechanism by which obesity affects male fertility. In this frame, the major challenge of this project is the identification of the main mechanisms underlying the complex interplay linking EVs-SPZ communication and obesity-male infertility by using transcriptomic, proteomic and sphingolipidomic approaches. The target of these studies will be SPZ, collected from obese subjects and from the epididymis of high diet feed (HDF) mice. Seminal fluid will be also evaluated as a source of EVs of various origins (mainly epididymosomes and prostasomes). Furthermore, we will explore a new class of non-coding RNAs (ncRNAs) as possible regulators of sperm quality, affected by unhealthy diet habits and obesity: the circular RNAs (circRNAs), physically and functionally interacting with microRNAs (miRNAs), thus constituting a ceRNET (circRNA-associated- competitive endogenous RNA network). CeRNET associated with ER stress, apoptosis and infertility will be validated in both experimental models. Finally, the proteomic and sphingolipidomic profiles of EVs will be dissected in order to identify proteins and bioactive sphingolipids shuttled to SPZ and displaying altered profiles in both obese infertile patients and the HDF-mouse model. Moreover, caput/cauda epithelial murine epididymal cells will be used to demonstrate the role of sphingolipid signalling in epididymosome sorting of the identified ncRNAs and proteins.

 

Data di avvio 30 Settembre 2023

Data di completamento 30 Settembre 2025

Total cost  € 63485,00

 

Progetto 20223H8LFM finanziato all’interno del Bando PRIN 2022 di cui al Decreto Direttoriale n. 104 del 02/02/2022 nell’ambito del Piano Nazionale di Ripresa e Resilienza, Missione 4 – Componente 2. Dalla Ricerca all’Impresa - Investimento 1.1 Fondo per il Programma Nazionale della Ricerca (PNR) e Progetti di Ricerca di Rilevante Interesse Nazionale (PRIN), finanziato dall’Unione europea – NextGenerationEU – CUP B53D23011130006