Tapeworm stem cells as drivers of regeneration and reproduction

摘要 寄生扁形虫，如绦虫，具有全球范围，并引起各种各样的症状， 肠道不适和嗜睡，器官衰竭，癫痫发作，甚至死亡。这些寄生虫有着复杂的生命 周期和非凡的能力的增长，繁殖，再生，和长寿。这些生理 特征是由干细胞实现的，因此了解这些寄生虫中的干细胞行为和调节， 能够发现广泛的潜在目标，可用于未来的药物开发。我 建立大鼠绦虫（Hymenolepis diminuta）作为易处理的现代模式生物的基础工作 我对这个系统中干细胞和再生的初步描述使它成为这项研究的理想选择。我的目标 是为了阐明这种绦虫干细胞驱动的再生和繁殖。我试图发现 调节干细胞能力并使绦虫节片再生成为可能， 生殖单位为此，我将鉴定干细胞亚群，并进行多能性功能测定。 利用创新的细胞分离和移植方法的潜力。我之前已经证明， 调节再生能力的微环境信号是向前偏置的。因此，我将承担高- 通量基因表达筛选和RNA干扰的靶向因子，极化沿沿着 前后轴穿过再生能力的绦虫颈部。此外，我将从功能上确定 生殖系谱系的遗传调节因子，并研究生殖细胞的潜在可塑性，以及它们的 与控制节片再生的机制协调。这些创新的研究利用了自然 寄生虫发展的进展，使遗传发现，并采取干细胞为中心的方法， 阐明寄生生物学。这是重要的，因为我将能够在两个茎和 生殖细胞生物学，以及在更大的疾病相关的背景下。

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.