The mechanism by which dying/apoptotic cells are cleared and how their clearance impacts the physiology and pathology of the male urogenital tract are important, yet is an understudied area. The seminiferous epithelium is a unique model system to study apoptotic cell clearance, and lessons learned from these studies will have important relevance in urogenital tract development and homeostasis. The proliferation and differentiation of germ cells is intimately tied to the death and removal of "unfit" germ cells. Th laboratories of the two Principal Investigators on this grant application are interested in the problem of cell clearance within the male tract and how this relates to the male gonadal function. We have previously reported a critical role for the engulfment protein ELMO1 and the Sertoli cell-mediated clearance of dying/apoptotic germ cells in the seminiferous epithelium. And we recently uncovered that perturbation of cell clearance in mice deficient in the mitochondrial protein UCP2 worsens the pathologic outcome of testicular torsion. This work defined the importance of cell clearance within the seminiferous epithelium and also underscored the need for further understanding the physiologic consequences of cell corpse clearance in the male urogenital tract. Our overall hypothesis is that specific signaling pathways critically regulate th removal apoptotic cells, and impacts normal testicular development, physiology, and pathology of the urogenital tract.
In Aim1 of this proposal, components upstream and downstream of ELMO1 that regulate cell clearance in the testes are investigated. Specifically, we address how BAI1, the receptor upstream of ELMO1, and RAC1 (the GTPase that is activated downstream of ELMO1), regulate cell clearance, using inducible and tissue specific knockout mice.
In Aim2 of this proposal, we address how the cell clearance in the urogenital tract regulates the blood testes barrier, which is important for establishing the integrity of the seminiferous epithelium an in preventing autoimmunity to testicular antigens. We also address whether enhancing engulfment (through transgenic overexpression of the engulfment receptor BAI1 in the Sertoli cells, and by compounds that decrease the mitochondrial membrane potential) would improve the clinical outcome from testicular torsion. Importantly, data from human testis biopsies collected after testicular torsion will be correlated with data from the mouse model. Collectively, the combination of in vitro and whole animal studies, focusing on specific molecules and pathways, will provide mechanistic insights governing cell corpse clearance and homeostasis in the male urogenital tract. Additionally, these studies could point toward enhancing cell clearance as a potential therapeutic modality for certain pathologies of the urogenital tract.
Every day billions of cells in our bodies die via apoptosis and their cellular corpses are removed quickly and silently. Recent exciting studies suggest that cell corpse clearance is a fundamental biologic process conserved through evolution from Caenorhabditis elegans to humans, and that perturbations of this process can lead to disruption of tissue homeostasis, inflammation, and autoimmune disorders. The results from the studies proposed in this application are expected to provide a better molecular and functional understanding of the development and integrity of the seminiferous epithelium, other aspects of testicular physiology and the adult urogenital tract. These results will have impact on human diseases of the male reproductive system such as autoimmune orchitis, acute injuries/pathologies to the urogenital tract.
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