The Biology of Stem Cells in the Human Parasite Schistosoma Mansoni

人类寄生虫曼氏血吸虫干细胞的生物学

• 批准号: 9207424
• 负责人: James J Collins
• 金额: $ 40.5万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-01 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9207424
• 关键词: Ablation; Address; Adult; Affect; Biological Process; Biology; Blood; Cells; Characteristics; Chronic; Data; Development; Disease; Electron Microscopy; Employee Strikes; Ensure; Environment; Foundations; Gene Expression; Genes; Genetic Transcription; Homeostasis; Human; Immune; Immune Evasion; Immune system; Immunity; Immunologics; In Situ Hybridization; Intestines; Knowledge; Life; Link; Longevity; Maintenance; Malaria; Methodology; Molecular; Molecular Analysis; Morphology; Mus; Muscle Cells; Natural regeneration; Operative Surgical Procedures; Organism; Parasites; Parasitic Diseases; Pathology; Pharmaceutical Preparations; Platyhelminths; Pluripotent Stem Cells; Population; Poverty; Praziquantel; Process; Property; Public Health; RNA Interference; Research; Role; Schistosoma; Schistosoma mansoni; Schistosomiasis; Stem cells; Stream; Surface; Testing; Tissues; Transplantation; base; cell behavior; combat; egg; experimental study; in vivo; innovation; insight; neglected tropical diseases; novel; novel therapeutic intervention; novel therapeutics; pathogen; programs; public health relevance; response; stem cell biology; stem-like cell

 DESCRIPTION (provided by applicant): Schistosomiasis is a neglected tropical disease that affects more than 200 million people in the developing world. Currently only a single drug (praziquantel) is available to treat this disease, highlighting the importance of studies aimed at understanding basic biological processes in these organisms. One remarkable characteristic of schistosomiasis is that the parasites responsible for this disease (i.e., schistosomes) can live in the blood stream of their human hosts for decades. How these parasites thrive in this immunologically hostile environment is not known. To address the longevity of these parasites in their mammalian host we previously demonstrated that schistosomes possess a population of somatic stem cells, which we refer to as neoblasts, which are capable of generating new intestine and muscle cells. Our preliminary studies for this proposal led us to a striking observation: a large fraction of these neoblasts differentiate to produce parts of the parasite's surface coat, a syncytial tissue known as the tegument. Our data suggest that tegumental cells are rapidly turned over, relying on neoblasts for their continuous renewal. As a result, many tegument-associated molecules are drastically down regulated within days following stem cell depletion. Since the tegument is the primary interface between the parasite and its host, understanding the stem cell-tegument relationship will provide important clues about how schistosomes defend themselves from immune attack. Based on these observations, we hypothesize that an important function of the neoblasts is to rapidly regenerate the parasite's tegument, thereby ensuring a functional host-parasite interface and evasion of host immunity. To address this hypothesis we propose the following two specific aims: (1) discover regulators of the neoblast-to-tegument transition and (2) understand the role for neoblasts in maintaining tegumental function in vivo. In the first aim, we will use transcriptional profiling and in situ hybridization to identify genes expressed in schistosome stem cells. We will then use RNA interference to determine which of these genes are required for the differentiation of the neoblasts into tegumental cells. In the second aim, we will use a combination of electron microscopy and immunological approaches to determine the effects that neoblast ablation has on tegumental morphology and function. Concurrently, we will surgically-transplant parasites incapable of making new tegumental cells into mice and examine the effects on worm survival. These studies are innovative as they are the first to explore the function of the neoblasts in the biology of this devastating parasite and bring a number of new methodologies to the table for studying these organisms. Collectively, these studies will determine how neoblasts contribute to parasite survival in the context of the host immune system, potentially leading to new therapeutic approaches targeting these important pathogens.

 描述（由申请人提供）：血吸虫病是一种被忽视的热带疾病，影响发展中国家2亿多人。目前只有一种药物（吡喹酮）可用于治疗这种疾病，突出了旨在了解这些生物体基本生物过程的研究的重要性。血吸虫病的一个显著特征是引起这种疾病的寄生虫（即，寄生虫）可以生活在 几十年来一直在人类宿主的血液中存活这些寄生虫如何在这种免疫敌对环境中茁壮成长尚不清楚。为了解决这些寄生虫在其哺乳动物宿主中的寿命问题，我们以前证明了寄生虫体具有一群体干细胞，我们称之为新母细胞，它们能够产生新的肠和肌肉细胞。我们对这一提议的初步研究使我们得到了一个惊人的观察结果：这些新成细胞中的很大一部分分化产生了寄生虫表面涂层的一部分，这是一种被称为皮层的合胞体组织。我们的数据表明，皮层细胞迅速翻转，依赖于新生细胞的持续更新。因此，许多与被膜相关的分子在干细胞耗竭后的几天内急剧下调。由于皮层是寄生虫与宿主之间的主要界面，因此了解干细胞-皮层关系将为寄生虫如何保护自己免受免疫攻击提供重要线索。基于这些观察结果，我们假设neoblast的一个重要功能是快速再生寄生虫的外皮，从而确保功能性宿主-寄生虫界面和逃避宿主免疫。为了解决这一假设，我们提出了以下两个具体目标：（1）发现新成细胞到皮层过渡的调节因子和（2）了解新成细胞在体内维持皮层功能中的作用。在第一个目标中，我们将使用转录谱和原位杂交来鉴定在染色体干细胞中表达的基因。然后，我们将使用RNA干扰来确定这些基因中的哪些基因是新成纤维细胞分化为表皮细胞所必需的。在第二个目标中，我们将使用电子显微镜和免疫学方法相结合，以确定新成纤维细胞消融对皮层形态和功能的影响。与此同时，我们将把不能制造新的被膜细胞的寄生虫移植到小鼠体内，并研究对蠕虫存活的影响。这些研究是创新的，因为它们是第一个探索neoblast在这种毁灭性寄生虫生物学中的功能，并为研究这些生物体带来了一些新的方法。总的来说，这些研究将确定neoblast如何在宿主免疫系统的背景下促进寄生虫的存活，从而可能导致针对这些重要病原体的新治疗方法。