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及其清除如何影响男性泌尿生殖道的生理学和病理学是重要的，但这是一个研究不足的领域。生精上皮是研究凋亡细胞清除的独特模型系统，从这些研究中吸取的经验教训将在泌尿生殖道发育和稳态中具有重要意义。生殖细胞的增殖和分化与“不合适”生殖细胞的死亡和去除密切相关。本基金申请的两位主要研究者的实验室对男性生殖道内细胞清除的问题以及这与男性性腺功能的关系感兴趣。我们以前曾报道了吞噬蛋白ELMO 1和支持细胞介导的死亡/凋亡的生精上皮中的生殖细胞的清除的关键作用。我们最近发现，线粒体蛋白UCP 2缺陷的小鼠细胞清除的扰动与睾丸扭转的病理结果有关。这项工作确定了生精上皮细胞清除的重要性，也强调了需要进一步了解男性泌尿生殖道细胞尸体清除的生理后果。我们的总体假设是，特定的信号通路严格调节th去除凋亡细胞，并影响正常的睾丸发育，生理和泌尿生殖道的病理。在本提案的目标1中，研究了ELMO 1上游和下游调节睾丸细胞清除的组分。具体来说，我们解决如何BAI 1，受体上游的ELMO 1，和RAC 1（GTdR，激活下游的ELMO 1），调节细胞清除，使用诱导型和组织特异性基因敲除小鼠。在本提案的目标2中，我们讨论了泌尿生殖道中的细胞清除如何调节血睾丸屏障，这对于建立生精上皮的完整性和防止对睾丸抗原的自身免疫非常重要。我们还讨论了增强吞噬（通过在支持细胞中过表达吞噬受体BAI 1的转基因，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。总的来说， 体外和整体动物研究的结合，集中于特定的分子和途径，将提供关于男性泌尿生殖道中细胞尸体清除和体内平衡的机制的见解。此外，这些研究可能指向增强细胞清除作为泌尿生殖道某些病理的潜在治疗方式。

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.