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Comparative systems biology of apicomplexan cell division

顶端复合体细胞分裂的比较系统生物学

基本信息

批准号：
10669790
负责人：
Manoj T Duraisingh
金额：
$ 132.72万
依托单位：
BOSTON COLLEGE
依托单位国家：
美国
项目类别：
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/10669790
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 Invaded Life Life Style Malaria Mammalian Cell Maps Mediating Modeling Mothers 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 comparative epigenomics experimental study flexibility gene network gene regulatory network inhibitor innovation interest knock-down network architecture novel nuclear division phenomenological models programs query tools single cell sequencing single-cell RNA sequencing software development tick transmission transcription factor transcriptome transcriptomics web app web site

项目摘要

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.

总结顶复门寄生虫对人类健康有重大影响，例如恶性疟原虫引起疟疾而弓形虫和巴贝虫属（Babyspp.）导致机会性感染。虽然这个紧密团结的团体它们共享专性的细胞内生活方式，它们显示出各种各样的无性细胞分裂模式。这些不同的寄生虫以及不同的生命阶段之间的一个单一的寄生虫物种，但开始- 并且终点总是具有宿主细胞侵袭能力的“子实体”。每一次分裂产生的子实体的数量变化很大（从2- 90，000），可以通过重新调整功能模块以几种不同的方式展开 1）母细胞骨架解体，2）DNA合成和染色体分离（D&S），3）核分裂，（4）子孢子组装（出芽）。顶复门中不同的细胞分裂模式来自于模块的顺序和次序以及模块重复的次数。在目前的模型中，细胞在转录波介导的转录因子中进行分裂，转录因子作用于靶基因，捆绑到功能模块中。然而，很少有人知道的组成，监管机构和布线的不同的模块，以及这如何导致Apicomplexa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的方法来回答，从寄生虫代表不同的多样性和“外来的”分裂细胞分裂模式，其中特定的模块，扩增，或以不同方式组合：分歧巴氏杆菌二分裂，恶性疟原虫双生殖，肉孢子虫 neurona endopolygenesis without karyokinesis，T. gondii无性endodytic和T.性前弓形虫在终末宿主中具有核分裂的内多发生。这种方法利用了单细胞测序革命结合计算网络分析方法。首先，单细胞将生成并分析五种细胞分裂模式的转录组学和表观基因组图谱，以确定包含在每个特定模块中的效应器。在表征较差的核分裂和细胞骨架分解模块将通过基因敲除进行实验验证。其次，化学和遗传扰动与单细胞测序相结合将使组装成为可能。因果基因调控网络（GRNs）跨越所有分裂模式。这些GRN中的候选模块控制器将通过重新编程和/或遗传扰动实验进行验证：改变（部分）分裂模式在特定的寄生虫。这项工作将回答有关apicomplexan具体生物学难以捉摸的问题在几乎没有研究的功能模块中，以及apicomplexan细胞分裂的灵活性是如何连接的。第三，拟议的工作将产生广泛的社区资源，包括单一表达和染色质五种不同细胞分裂模式和寄生虫物种的可访问性地图集。此外，数据集将可通过基于Web的应用程序在真实的时间内跨系统搜索任何感兴趣的生物特征，将其并入VEuPathDB中，并能够查询细胞分裂以外的生物学问题的数据。