Tapeworm stem cells as drivers of regeneration and reproduction

摘要 寄生扁虫，如绦虫，在全球范围内传播，并从 肠道不适和昏昏欲睡导致器官衰竭、癫痫发作，甚至死亡。这些寄生虫有着复杂的生命 周期和非凡的生长、繁殖、再生和长寿的能力。这些生理上的 特征是由干细胞实现的，因此了解干细胞在这些寄生虫中的行为和调节 发现可用于未来药物开发的广泛潜在目标的能力。我的 建立鼠带绦虫作为易驯化的现代模式生物的基础工作 我对干细胞的初步描述和在这个系统中的再生使它成为这项研究的理想选择。我的目标 是为了阐明干细胞驱动的这种绦虫的再生和繁殖。我试图发现这些信号 调节干细胞能力并使绦虫节节再生成为可能，每个节节都是一种功能 生殖单位。为此，我将鉴定干细胞亚群，并对多能性进行功能分析。 使用创新的细胞分离和移植方法具有潜力。我之前已经证明过 调节再生能力的微环境信号是偏向的。因此，我将承担高- 靶向极化因子的基因表达筛选和RNA干扰 横跨有再生能力的绦虫颈部的前后轴线。此外，我将在功能上确定 和研究生殖细胞的潜在可塑性，以及它们的 与管理孕节再生的机制协调。这些创新的研究利用了自然的 寄生虫发展的进展，以进行基因发现和采取以干细胞为中心的方法 阐明寄生虫生物学。这是有意义的，因为我将能够在茎和茎中做出根本性的发现 生殖细胞生物学，以及在更大的与疾病相关的背景下。

Abstract Parasitic flatworms, such as tapeworms, have global reach and cause a wide variety of symptoms from intestinal distress and lethargy to organ failure, seizures, and even death. These parasites have complex life cycles and a remarkable capacity for growth, reproduction, regeneration, and longevity. These physiological traits are enabled by stem cells, thus understanding stem cell behaviors and regulation in these parasites has the capacity to uncover a broad range of potential targets that can be exploited for future drug development. My foundational work establishing the rat tapeworm, Hymenolepis diminuta, as a tractable modern model organism and my initial characterization of stem cells and regeneration in this system make it ideal for this study. My goal is to elucidate stem cell-driven regeneration and reproduction in this tapeworm. I seek to discover the signals that regulate stem cell potency and enable regeneration of tapeworm proglottids, which are each a functional reproductive unit. To this end, I will identify subpopulations of stem cells and functionally assay for pluripotent potential using innovative cell isolation and transplantation methodologies. I have previously shown that microenvironmental signals that regulate regenerative ability are anteriorly biased. Thus, I will undertake high- throughput gene expression screening and RNA interference by targeting factors that are polarized along the anterior-posterior axis across the regeneration-competent tapeworm neck. Furthermore, I will functionally identify genetic regulators of the germline lineage and investigate the potential plasticity of germ cells, as well as their coordination with mechanisms that govern proglottid regeneration. These innovative studies exploit the natural progression of parasite development to make genetic discoveries and take a stem cell-centric approach to illuminate parasite biology. This is significant as I will be able to make fundamental discoveries in both stem and germ cell biology, as well as in a greater disease-relevant context.