Cell Clearance in Urogenital Tract

泌尿生殖道细胞清除

• 批准号: 8841611
• 负责人: JEFFREY J LYSIAK
• 金额: $ 31.97万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-15 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8841611
• 关键词: Acute; Address; Adult; Animals; Antigens; Apoptosis; Apoptotic; Applications Grants; Area; Autoimmune Diseases; Autoimmune orchitis; Autoimmunity; BAI1 gene; Binding; Biological Assay; Biological Models; Biopsy; Blood-Testis Barrier; Caenorhabditis elegans; Cells; Cessation of life; Clear Cell; Clinical; Complex; Coupled; Cytoskeletal Modeling; DOCK1 gene; Data; Development; Engineering; Epithelium; Equilibrium; Evolution; Excision; Genes; Genitourinary system; Germ Cells; Guanosine Triphosphate Phosphohydrolases; Homeostasis; Human; In Vitro; Inflammation; Injury; Knockout Mice; Knowledge; Laboratories; Lead; Learning; Life; Link; Male Genital Organs; Mediating; Membrane Potentials; Mitochondrial Proteins; Modality; Molecular; Monomeric GTP-Binding Proteins; Mus; Nature; Outcome; Pathologic; Pathology; Pathway interactions; Phagocytes; Phosphatidylserines; Physiological; Physiology; Principal Investigator; Process; Proteins; Reperfusion Injury; Reporting; Role; Signal Pathway; Signal Transduction; Spermatic Cord Torsion; Testing; Testis; Therapeutic; Tissue Sample; Tissues; Torsion; Transgenic Organisms; Work; gonad function; human data; human disease; human tissue; improved; in vivo; insight; interest; male; mitochondrial membrane; mouse model; overexpression; phosphatidylserine receptor; prevent; receptor; sertoli cell; spermatogenic epithelium structure

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.

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学很重要，但仍是一个尚未充分研究的领域。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“不合格”生殖细胞的死亡和去除密切相关。本次拨款申请的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。我们之前报道过吞噬蛋白 ELMO1 和支持细胞介导的生精上皮死亡/凋亡生殖细胞清除的关键作用。我们最近发现，线粒体蛋白 UCP2 缺陷小鼠的细胞清除扰动会恶化睾丸扭转的病理结果。这项工作定义了生精上皮细胞清除的重要性，并强调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，特定的信号传导途径关键性地调节凋亡细胞的清除，并影响正常的睾丸发育、泌尿生殖道的生理学和病理学。在该提案的目标 1 中，研究了调节睾丸细胞清除的 ELMO1 上游和下游组件。具体来说，我们使用诱导型和组织特异性敲除小鼠来探讨 BAI1（ELMO1 上游的受体）和 RAC1（ELMO1 下游激活的 GTP 酶）如何调节细胞清除。在该提案的目标 2 中，我们讨论了泌尿生殖道中的细胞清除如何调节血睾屏障，这对于建立生精上皮的完整性和防止睾丸抗原的自身免疫非常重要。我们还探讨了增强吞噬（通过支持细胞中吞噬受体 BAI1 的转基因过度表达，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， 体外研究和整体动物研究相结合，重点关注特定分子和途径，将为控制男性泌尿生殖道中的细胞尸体清除和稳态提供机制见解。此外，这些研究可能表明增强细胞清除作为泌尿生殖道某些病理的潜在治疗方式。