The spatial organization of the Plasmodium genome throughout its infectious cycle

疟原虫基因组在整个感染周期中的空间组织

基本信息

批准号：
8675801
负责人：
Karine Gaelle Le Roch
金额：
$ 45.5万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-07 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8675801
关键词：
Accounting Agreement Antibodies Antimalarials Architecture Area Biology Cell Cycle Cell Nucleus ChIP-seq Chromatin Chromatin Structure Chromosome Structures Communicable Diseases Computer Simulation Computer software Computing Methodologies DNA DNA Sequence DNA Structure DNA-Binding Proteins Data Data Set Development Disease Drug Design Drug Targeting Epigenetic Process Erythrocytes Event Exhibits Gene Expression Gene Expression Regulation Genes Genetic Transcription Genome Genomic DNA Genomics Goals Human Human Genome Laboratories Life Cycle Stages Machine Learning Malaria Maps Measurement Messenger RNA Metabolic stress Methodology Methods Microscopy Modeling Molecular Molecular Profiling Nuclear Nucleosomes Organism Parasite Control Parasite resistance Parasites Pattern Pharmaceutical Preparations Phase Plasmodium Plasmodium falciparum Play Publishing Research Personnel Resolution Role Series Staging Structure Techniques Technology Time Time Series Analysis Transcriptional Regulation Vaccines Variant Virulence Virulent base combat computerized tools design genome-wide histone modification improved in vivo innovation insight novel novel therapeutic intervention novel therapeutics predictive modeling public health relevance response three dimensional structure three-dimensional modeling tool transcription factor vaccine development

项目摘要

DESCRIPTION (provided by applicant): Malaria remains one of the most deadly infectious diseases in the developing world. The absence of a vaccine and the development of parasite resistance to commonly used antimalarial drugs underscore the urgent need for new therapeutic approaches. The goal of this project is to generate insights into the mechanisms whereby Plas- modium falciparum, the parasite responsible for the most virulent form of malaria, regulates its genes' expression throughout its life cycle. Mechanisms controlling gene expression in the parasite are still poorly understood. Increasing evidence indicates that control of gene expression in Plasmodium occurs at multiple levels, via local protein-DNA binding events, patterns of histone modifications, local chromatin structure and nucleosome occupancy, and large-scale chromatin structure. A variety of existing genome-wide data sets, including the genomic DNA sequence as well as measurements of RNA expression levels and nucleosome occupancy, provide insight into many aspects of this regulatory machinery. However, a global picture of the structure of DNA in the nucleus of the parasite is not yet available. This project will apply a recently developed technology to map in Plasmodium all intra- and inter-chromosomal interactions at kilobase resolution throughout the parasite life cycle. These data will be used to build a dynamic three-dimensional model of the Plasmodium genome in vivo. The project will also generate a series of maps of histone modifications genome-wide. Finally, these two new data sets, along with existing data sets, will be integrated using machine learning methods to produce a predictive model of gene expression across the Plasmodium eryrthrocytic cycle. Rational drug design requires a detailed understanding of the molecular basis of disease. By providing fundamental insight into the regulatory mechanisms of the malaria parasite, this project will improve our ability to design new drugs and novel lines of defense against malaria.

描述（由申请人提供）：疟疾仍然是发展中国家最致命的传染病之一。缺乏疫苗以及对常用抗疟药的寄生虫耐药性的发展强调了对新治疗方法的迫切需求。该项目的目的是生成对疟原虫（负责疟疾形式最具毒性形式的寄生虫）的机制的见解，该机制在整个生命周期中调节其基因的表达。控制寄生虫基因表达的机制仍然很少了解。越来越多的证据表明，通过局部蛋白-DNA结合事件，组蛋白修饰的模式，局部染色质结构和核小体占用率以及大规模的染色质结构，对疟原虫中基因表达的控制发生在多个水平上。各种现有的全基因组数据集，包括基因组DNA序列以及RNA表达水平和核小体占用的测量，可深入了解该调节机制的许多方面。但是，尚不可用的寄生虫核中DNA结构的全球图片。该项目将应用最近开发的技术在整个寄生虫生命周期中以千目标分辨率以kilobase分辨率绘制疟原虫中的所有染色体内和染色体间相互作用。这些数据将用于构建体内疟原虫基因组的动态三维模型。该项目还将生成一系列整个基因组的组蛋白修饰图。最后，这两个新数据集以及现有的数据集将使用机器学习方法集成，以在整个疟原虫递归疟原虫循环中产生基因表达的预测模型。理性药物设计需要详细了解疾病的分子基础。通过提供对疟疾寄生虫的监管机制的基本见解，该项目将提高我们设计新药和针对疟疾的新型防御线的能力。