Cell Clearance in Urogenital Tract

描述（由申请人提供）：死亡/凋亡细胞被清除的机制以及它们的清除如何影响男性泌尿生殖道的生理和病理是重要的，但仍是一个研究不足的领域。精原上皮是研究凋亡细胞清除的独特模型系统，从这些研究中获得的经验教训将对泌尿生殖道发育和体内平衡具有重要意义。生殖细胞的增殖和分化与“不合适”生殖细胞的死亡和移除密切相关。两位首席研究员的实验室对男性生殖道内的细胞清除问题及其与男性性腺功能的关系感兴趣。我们之前报道了吞噬蛋白ELMO1和支持细胞介导的精原上皮中死亡/凋亡生殖细胞清除的关键作用。我们最近发现，在线粒体蛋白UCP2缺乏的小鼠中，细胞清除的扰动恶化了睾丸扭转的病理结果。这项工作明确了精系上皮细胞清除的重要性，也强调了进一步了解男性泌尿生殖道细胞尸体清除的生理后果的必要性。我们的总体假设是，特定的信号通路对凋亡细胞的清除起着关键的调节作用，并影响睾丸的正常发育、泌尿生殖道的生理和病理。在本提案的目的1中，研究了睾丸中调节细胞清除的ELMO1的上游和下游成分。具体来说，我们利用诱导型和组织特异性敲除小鼠，研究了ELMO1上游受体BAI1和ELMO1下游激活的GTPase RAC1如何调节细胞清除。在本提案的目的2中，我们讨论了如何在泌尿生殖道细胞清除调节血睾丸屏障，这对于建立精系上皮的完整性和防止睾丸抗原的自身免疫是重要的。我们还讨论了增强吞噬（通过在支持细胞中转基因过表达吞噬受体BAI1，以及通过降低线粒体膜电位的化合物）是否会改善睾丸扭转的临床结果。重要的是，睾丸扭转后收集的人类睾丸活检数据将与小鼠模型的数据相关联。总的来说,

DESCRIPTION (provided by applicant): 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.