Functional analysis of androglobin, a novel oxygen-binding protein associated with male infertility.

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Hemoglobin and myoglobin represent the two most-established oxygen-binding respiratory proteins. The post-genomic era revealed the presence of additional mammalian globin types, including neuroglobin and cytoglobin. Recently, the applicants identified a novel highly conserved globin lineage, consisting of large chimeric proteins with an N-terminal protease domain and a central globin domain, named androglobins (Adgbs) because of their specific expression in testis tissue. Preliminary characterization of a newly generated Adgb-deficient mouse model suggests a developmental defect during spermatogenesis. The present collaborative project will comprehensively explore the physiological role, gene regulation and biomedical implications of Adgb using in vivo as well as in vitro approaches. Based on the infertility phenotype of Adgb, we will initially focus on the testis-specific role of Adgb, employing testes and sperm histology, sperm functionality assays, transcriptomics and interactome studies to characterize the knock-out phenotype. Biophysical and biochemical studies will help clarifying hypothetical enzymatic or signaling roles of Adgb. For this purpose we will use cell culture studies to genetically modify expression levels enabling functional studies to evaluate a potential anti-oxidative role of Adgb. Furthermore, we will determine the subcellular localization of Adgb and characterize the physico-chemical properties of recombinantly expressed Adgb. Finally, the gene regulation of Adgb will be addressed using reporter gene assays and epigenetic approaches in order to investigate the modulation of Adgb expression under pathological conditions. Collectively, our studies will likely contribute to an improved understanding of male infertility.