Comparative systems biology of apicomplexan cell division

顶端复合体细胞分裂的比较系统生物学

• 批准号: 10539938
• 负责人: Manoj T Duraisingh
• 金额: $ 141.38万
• 依托单位: BOSTON COLLEGE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-21 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10539938
• 关键词: Apical; Apicomplexa; Atlases; Babesia; Babesiosis; Biological; Biology; Cell Cycle; Cell Cycle Progression; Cell division; Cells; Cellular Assay; Chemicals; Chromatin; Chromosome Segregation; Communities; Computer software; Cyclin-Dependent Kinases; Cyclins; Cytoskeleton; DNA biosynthesis; Data; Data Set; Family; Gene Expression; Gene Expression Profile; Genes; Genetic; Genetic Transcription; Health; Heart; Homologous Gene; Human; Life; Life Style; Malaria; Mammalian Cell; Maps; Mediating; Modeling; Mothers; Online Systems; Opportunistic Infections; Organelles; Parasites; Pathogenesis; Pathway Analysis; Pharmaceutical Preparations; Plasmodium; Plasmodium falciparum; Research; Resolution; Resources; Sarcocystis; Surveys; System; Systems Biology; Time; Toxoplasma gondii; Toxoplasmosis; Transposase; Variant; Visualization; Work; asexual; causal variant; chemical genetics; comparative; epigenomics; experimental study; flexibility; gene network; gene regulatory network; inhibitor; innovation; interest; knock-down; network architecture; novel; nuclear division; programs; query tools; single cell sequencing; single-cell RNA sequencing; software development; tick transmission; transcription factor; transcriptome; transcriptomics; web site

Summary Apicomplexan parasites have major impacts on human health e.g. Plasmodium falciparum causes malaria whereas Toxoplasma gondii and Babesia spp. cause opportunistic infections. Although this close-knit group shares their obligate intracellular life styles, they display a wide variety of asexual cell division modes. These differ between parasites as well as between different life stages within a single parasite species, but the start- and end-point is always a host cell invasion competent ‘zoite’. The number of zoites made per division round varies dramatically (from 2-90,000) and can unfold in several different ways by reshuffling the functional modules of 1) mother cytoskeleton disassembly, 2) DNA synthesis and chromosome segregation (D&S), 3) karyokinesis, and 4) zoite assembly (budding). Distinct cell division modes across Apicomplexa arise from variations in the order and sequence of the modules as well as the number of module repetitions. In the current model, cell division progresses in transcriptional waves mediated transcription factors that act on target genes that in turn bundle into the functional modules. However, little is known of the composition, regulators and wiring of the different modules, and how this leads to the diversity of cell division modes in Apicomplexa. The research team hypothesizes that these questions can be answered by a comparative systems biology approach, starting with parasites representing different diverse and ‘exotic’ division cell division modes wherein particular modules are amplified, or combined differently: Babesia divergens binary fission, P. falciparum schizogony, Sarcocystis neurona endopolygeny without karyokinesis, T. gondii asexual endodyogeny and T. gondii pre-sexual endopolygeny with karyokinesis in the definitive host. This approach takes advantage of the single cell sequencing revolution combined with computational network analysis approaches. Firstly, single cell transcriptomic and epigenomic maps of the five cell division modes will be generated and analyzed to define the effectors contained in each specific module. A subset of uncharacterized effectors in the poorly characterized karyokinesis and cytoskeleton disassembly modules will be experimentally validated by gene knock-downs. Secondly, chemical and genetic perturbations combined with single cell sequencing will enable the assembly of causal gene regulatory networks (GRNs) across all division modes. Candidate module controllers in these GRNs will be validated by reprogramming and/or genetic perturbation experiments: changing (parts of) the division mode in specific parasites. This work will answer elusive questions regarding apicomplexan specific biology within barely studied functional modules, as well as how apicomplexan cell division flexibility is wired. Thirdly, the proposed work will produce extensive community resources comprising single expression and chromatin accessibility atlases across five different cell division modes and parasite species. Moreover, data sets will be searchable across systems in real time for any biological feature of interest by web-based Apps that will be incorporated in VEuPathDB and enable querying the data for biological questions beyond cell division.

概括 Apicomplexan寄生虫对人类健康有重大影响，例如恶性疟原虫会导致疟疾 而弓形虫弓形虫和巴贝西亚属。引起机会性感染。虽然这个紧密联系的小组 分享其义务的细胞内生活方式，显示出各种各样的无性细胞分裂模式。这些 寄生虫以及单个寄生虫种类的不同生命阶段之间的不同之处，但开始 终点始终是宿主细胞入侵胜任的“ Zoite”。每场比赛的Zoite数量 急剧变化（从2-90,000起），可以通过重新装修功能模块来以几种不同的方式展开 1）母细胞骨架拆卸，2）DNA合成和染色体隔离（D＆S），3）核酸类药物， 4）Zoite组装（萌芽）。跨apicomplexa的不同细胞分裂模式来自于 模块的顺序和顺序以及模块重复的数量。在当前模型中 分裂在转录波中介导的转录因子的进展，这些转录因子作用于靶基因 束进入功能模块。但是，关于组成，调节器和布线知之甚少 不同的模块，以及这如何导致apicomplexa中细胞分裂模式的多样性。研究团队 假设这些问题可以通过比较系统生物学方法来回答 代表不同的潜水员和“异国”分区分区模式的寄生虫，其中特定模块是 放大或组合不同：Babesia Divergens二进制裂变，恶性杆菌精神分裂症，肌囊肿 Neurona Enderygeny没有核酸核酸，T。Gondii无性内dododododogeny和T. gondii前性疾病 在确定的宿主中，具有核金油素的核能。这种方法利用单个单元格 测序革命与计算网络分析方法相结合。首先，单个单元格 将生成五个细胞分裂模式的转录组和表观基因组图，并分析以定义 每个特定模块中包含的效果。在较差的特征中，未表征的效果的子集 核酸和细胞骨架拆卸模块将通过基因敲除实验验证。 其次，化学和遗传扰动与单细胞测序相结合将使组装能够组装 所有分裂模式的因果基因调节网络（GRN）。这些GRN中的候选模块控制器 将通过重编程和/或遗传扰动实验来验证：更改（部分） 特定寄生​​虫的模式。这项工作将回答有关Apicomplexan特定生物学的难以捉摸的问题 在几乎没有研究的功能模块中，以及如何连接apicomplexan细胞分裂柔韧性。第三， 拟议的工作将产生广泛的社区资源，以编译单一表达和染色质 跨五种不同细胞分裂模式和寄生虫物种的可访问性图谱。此外，数据集将是 可以实时搜索跨系统，以获取基于Web的应用程序感兴趣的任何生物学特征 纳入VEUPATHDB并启用数据以外的生物学问题以外的生物学问题。