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It is now generally accepted that a sperm-specific epigenetic code is established during spermiogenesis and transmitted to the oocyte. Aberrations may represent one reason for idiopathic male infertility resulting in decreased IVF/ICSI outcome. In a previous study, gene promoters associated with histone H4 acetylated at lysine 12 (H4K12ac) and also exonicsequences associated with histone H3 acetylated at lysine 9 (H3K9ac) have been identified in ejaculated spermatozoa from fertile donors and subfertile patients applying ChIP-on-chip HG18 promoter array and ENCODE array, respectively.
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In the testis clusterin (syn: ApoJ, Sp-40, TRPM-2, SGP-2) is involved in sperm maturation, (anti-) apoptosis, lipid transport, cell aggregation and cell adhesion. The Sertoli cells are the primary source of clusterin which can be modulated by testosterone or transforming growth factor (TGF)-betas. Extracellular clusterin enhances Sertoli cell aggregation, but the biological effects of intracellular clusterin have not been studied to date in Sertoli cells.
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Human disorders with peroxisomal deficiency show a range of testicular pathologies leading to male infertility, the molecular pathogenesis of which is not yet understood. We have therefore characterised peroxisomes and identified a strong heterogeneity of peroxisomal protein composition in distinct cell types of mouse and human testis and revealed that Sertoli cell peroxisomes are essential for the maintenance of regular spermatogenesis and the overall regulation of gonadal steroid metabolism.
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Project 4 for the first time will study the role of contractile cells known to affect spermatogenesis and to be involved in the transport of spermatozoa from the testis to the epididymis for their contribution to male infertility. In particular, this project focuses on the part played by phosphodiesterases (PDEs) and the cGMP pathway on sperm transport and spermatogenesis.
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E. coli based infection is an established major factor for male infertility. In Sertoli cells (SC), peritubular cells (PTC) and testicular macrophages (TM) the pro-inflammatory NFκB pathway is blocked downstream at different levels following infection with uropathogenic E. coli (UPEC) resulting in inhibited secretion of pro-inflammatory cytokines. Infected cells respond with nuclear factor of activated T cells (NFAT)C2 signaling as alternative pathway, however, leading to an anti-inflammatory Th2 type response.
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The chromatin of mature spermatozoa is characterized by a dual protamine/nucleosome structure. Recent studies provide hints that somatic-like histones within the sperm exhibit specific ´codes´ (posttranslational acetylation, mono-, di- or trimethylation on different lysine residues) and associate mainly with hypomethylated promoters of development relevant genes. The common hypothesis is that sperm histones and their ´codes´ are transmitted to the oocyte together with the paternal haploid genome and are crucial for transcriptional activation during early embryogenesis.
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Sperm morphogenesis is largely based on translationally repressed stored mRNAs in mammals, as well as in the model organism Drosophila. In Drosophila, five testis-specific TATA-box binding protein (TBP)-associated factors (tTAFs) have been identified which control activation of differentiation-relevant genes. All target genes known so far are solely transcribed in a single cell type, namely spermatocytes, and kept in a repressive status in all other cell types - presumably by polycomb complexes
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Generally, age-related testicular changes are associated with an increase of germ cell degeneration, decline of spermatogenesis and androgen decline resulting in a gradual decrease of sperm count. Unfortunately, an association of these findings to vascular atherosclerotic alterations has never been investigated systematically, although arterial lesions in testicular biopsies of azoospermic men have been described already 30 years ago.
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Project Z administers the Clinical Research Unit and coordinates the research activities between principal investigators. Furthermore, management of investment, office supplies, travel expenses and costs for guest researchers will be assigned to project Z.
