Periodic Reporting for period 1 - INFISS (Targeting infertility associated to defective Insulin/IGF-1 signalling)
Periodo di rendicontazione: 2017-05-01 al 2018-10-31
Polycystic ovary syndrome (PCOS) is the most common endocrine abnormality of reproductive-aged women today, affecting approximately 6.6% of unselected reproductive-aged women. This disease is closely related to diabetes with two-thirds of adult women with PCOS suffering from insulin resistance and hyperinsulinemia. Although there are pharmacological interventions to reduce the symptoms, there is no cure for this disease. In this project, we aimed at identifying gene targets that could putatively be used to treat PCOS and test some known inhibitory drugs for those genes.
The insulin/insulin-like growth factor signalling (IIS) pathway is well conserved among all metazoans, and reduction of function of this pathway by mutation generates infertility in all the organisms studied. In this project, we used mutants of the IIS pathway of the nematode Caenorhabiditis elegans to model PCOS. These mutants have a significant decrease of fertility. In this background, we reduced by RNAi the activity of most of the nematode genes having a human orthologue, finding that reduction of 27 genes generate an increase of fertility in two different mutants of the IIS. This result suggests that their human orthologue gene could be targeted by inhibitory drugs to treat PCOS. We have tested some known drugs that inhibit 6 of those genes but no drug or combination of drugs suppressed the infertility of our models. These results indicate that inhibiting the gene function of the identified targets could be an approach to treat this disease but new drugs need to be design to make sure they specifically inhibit the gene products. We also suggest the best gene candidates for this design, which should be those that can suppress more than one mutant strain of the nematode PCOS models, their expression need to be higher in the nematode model versus wild type animals, and correlation must exist with the expression levels of that particular target in humans. We identified 4 genes that are overexpressed in both, nematodes and PCOS patients, and that when inactivated in the nematode suppress infertility.
The insulin/insulin-like growth factor signalling (IIS) pathway is well conserved among all metazoans, and reduction of function of this pathway by mutation generates infertility in all the organisms studied. In this project, we used mutants of the IIS pathway of the nematode Caenorhabiditis elegans to model PCOS. These mutants have a significant decrease of fertility. In this background, we reduced by RNAi the activity of most of the nematode genes having a human orthologue, finding that reduction of 27 genes generate an increase of fertility in two different mutants of the IIS. This result suggests that their human orthologue gene could be targeted by inhibitory drugs to treat PCOS. We have tested some known drugs that inhibit 6 of those genes but no drug or combination of drugs suppressed the infertility of our models. These results indicate that inhibiting the gene function of the identified targets could be an approach to treat this disease but new drugs need to be design to make sure they specifically inhibit the gene products. We also suggest the best gene candidates for this design, which should be those that can suppress more than one mutant strain of the nematode PCOS models, their expression need to be higher in the nematode model versus wild type animals, and correlation must exist with the expression levels of that particular target in humans. We identified 4 genes that are overexpressed in both, nematodes and PCOS patients, and that when inactivated in the nematode suppress infertility.