According to WHO reports, over 10% of women in reproductive age (20-44y) are infertile or subfertile. Oocyte quality is one of the major causes of infertility, as evident in several metabolic diseases such as obesity and type II diabetes, as well as aging. During the last 5-7 years a substantial scientific evidence has been built in our research unit focusing on maternal metabolic health in relation to oocyte and embryo quality. We showed evidence that the ovarian follicular microenvironment is significantly altered under the influence of metabolic disorders leading to a direct detrimental lipotoxic impact on the oocyte, manifested by oxidative stress, mitochondrial dysfunction, endoplasmic reticulum (ER) stress and apoptosis. This fundamental knowledge should now form the basis to design a sustainable treatment or prevention strategy. There is a large need for safe drug formulations that can reach the oocyte and particularly influence mitochondrial and ER functions, with high bioavailability and efficiency. Targeting these pathways and organelles usually require the use of hydrophobic compounds. In addition, the oocyte is surrounded by several cumulus cell layers and a glycoprotein layer (zona pellucida) which form biological barriers. At the subcellular level, drug delivery to the mitochondria (such as antioxidants) is another challenge due to the complex inner membrane network structure, unusual phospholipid, Cardiolipin, and a strong negative charge.
Information about clathrin- and caveolin-mediated endocytosis in mammalian oocytes, and subsequent formation of endosomes and liposomal degradation are very scarce. Studying these mechanisms and understanding the role gap junctional communication in delivering molecules from cumulus cells (CCs) to the oocyte may facilitate delivery of therapeutics or protective compounds to the ooplasm. This can be combined with strategically designed formulations of e.g. antioxidants to target defective organelles, such as mitochondrial and endoplasmic reticulum, and to reduce oxidative stress at the subcellular level. Our preliminary proteomics data show that proteins related to these endocytosis mechanisms are expressed in oocytes and cumulus cells, and are affected by oocyte quality, cellular metabolic stress and the microenvironment in which an oocyte is matured. The present project proposal aims to take the first steps in understanding the role of these proteins in mediating uptake of nutrients and other compounds in oocytes and CCs. This will be investigated by gene and protein expression analysis at different time points, uptake of trace molecules and using specific inhibitors of each mechanism. The effect of the latter on oocyte developmental competence will be examined. With this approach we aim to provide new fundamental knowledge that may increase treatment efficiency of enhance oocyte quality and fertility.