Project Portugal 2030

Summary

The SYNAPTONEMAL COMPLEX (SC) is a highly conserved proteinaceous scaffold that is assembled during meiosis between paired homologous chromosomes. SC stabilizes chromosome pairing interactions and is required for synapsis formation and meiotic recombination. Defects in the SC have been associated to reduced crossing over, chromosomal nondisjunction and reduced fertility in worms, fruit flies (Drosophila melanogaster), mouse and humans, among many other organisms. In humans, mutations in different components of the SC have been associated with both male and female infertility, including conditions such as azoospermia, recurrent pregnancy loss, and premature ovarian insufficiency [5, 6]. This link is often attributed to an elevated occurrence of chromosome nondisjunction and genomic instability. Despite these associations, effective therapeutic approaches for managing SC misregulation are still lacking. Recent findings from our team suggest that the SC can also function as a regulator of germ line gene expression, potentially through crosstalk with Polycomb repressive complexes (Martinho, unpublished) (Fig. 19). This was previously UNKNOWN, and most likely is a contributing factor to the pathologies associated with SC defects. We HYPOTHESIZE that the identification of germ line genes whose expression is regulated by the SC and whose function is required for primary oocyte determination will provide a window of opportunity for novel prophylactic and therapeutic approaches capable of managing female infertility. To attain this goal, we outline the following SPECIFIC OBJECTIVES: Examination of the regulatory roles of the Synaptonemal Complex (SC) in germ line gene expression and define their implications for female fertility: 1) Identification of Drosophila Germ Line Genes Regulated by the Synaptonemal Complex and Whose Function is required for oocyte Determination. (Tasks 1-4 and Task 5) 2) Defining if the Temporal and Spatial Regulation Germ line Gene Expression is Regulated by the Synaptonemal Complex. (Task 6) 3) Identification of Drosophila Germ Line Genes whose Mammalian orthologs are similarly expressed in the Ovaries during Oocyte determination. (Task 7) Use of this knowledge to identify novel druggable genes aiming for potential prophylactic/ therapeutic interventions to manage female infertility: 4) Identification of Druggable Drosophila Germ Line Genes Aiming for Potential Therapeutic Interventions Related to Infertility. (Tasks 5-7) Use of this knowledge to perform a targeted Drosophila-based proof-of-concept drug screen for compounds capable of suppressing the infertility phenotypes associated to SC misregulation: 5) Identification of at least one Lead Compound Potentially Capable of Mitigating Female Infertility due to SC misregulation. (Task 8) The identification of lead compounds capable of mitigating the consequences of SC misregulation during the determination of the primary oocytes is likely to give a significant contribution for the development of novel prophylactic and therapeutic approaches to manage female infertility. Note to the Reviewers: To help readability, a full copy of this grant, with references, figures, letters of support and detailed curriculum vitae is available as a PDF.