TUBITAK Project, 2021 - 2024
Bacterial infections are among the most important causes of infertility in humans as well as in animals. Gram-negative and-positive bacteria are the most frequently isolated pathogens in the uterus and mammary gland infections that cause infertility in humans and domestic animal species. These animals show fertility problems not only during the infection but also after the resolution of the infection and this causes great economic losses. Although these infections occur in distant organs such as the uterus and mammary gland from the ovary, metritis, and mastitis perturb follicle development as well as ovarian function. While the luteal cells, follicles, and endothelial cells in the ovary express the toll-like receptor 2 (TLR2) and TLR4, which recognize gram-negative and-positive bacterial toxins and cause the onset of the inflammatory response, the molecular mechanism of reduction of infection-associated follicular cells in the ovary has not been understood yet. Recently, Lipopolysaccharide (LPS) associated reduction in the primordial follicle pool was shown in the murine ovary in vivo (Bromfield ve Sheldon, 2011). Similarly, we were able to show that LPS disrupts in vitro capillary morphogenesis and endothelial barrier function without activating apoptosis (Gram vd., 2019). This led us to the hypothesis that reduction in the number of the primordial follicle and disrupted in vitro capillary morphogenesis and endothelial barrier function due to inflammatory changes can be caused by the activation of gram-negative and-positive bacterial toxin-mediated autophagy in the ovary. Therefore, in order to explain our hypothesis, the aim of the proposed project is to further investigate the molecular mechanisms of autophagy associated LPS and Pam3-Cys-Ser-Lys4 (Pam3CSK4) -induced disruption in the ovary, granulosa cells, and ovine luteal endothelial cells (OLENDO) using real-time PCR, western methods, immunofluorescence and gap junctional intercellular communication methods in 3 year period. Additionally, using similar technics the effect of bacterial toxins on ovarian function will be investigated in vivo in mice.
The information that will be acquired from this project allowing a better understanding of the molecular mechanism of the gram-negative and positive bacteria toxins associated infertility due to follicular atresia connected reduction in the primordial follicle pool in humans as well as in domestic animal species. Importantly, the results achieved during this project will be used as a basis for the development of new treatment strategies for infertility in humans as well as in domestic animal species.