ConProject-001

ConProject-001

• 批准号: 10226178
• 负责人: Christine E Heitsch
• 金额: $ 33.7万
• 依托单位: GEORGIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226178
• 关键词: 3-Dimensional; Address; Adopted; Alphavirus; Animals; Automobile Driving; Base Pairing; Base Sequence; Biochemistry; Biological; Capsid; Chemicals; Code; Collaborations; Combinatorics; Communities; Complex; Computer Analysis; Computing Methodologies; Coupled; Cryoelectron Microscopy; Disease; Disease Outbreaks; Elements; Evolution; Family; Gene Expression; Genome; Genomics; Human; Immune Evasion; Individual; Investigation; Magnetic Resonance Imaging; Maps; Mathematics; Messenger RNA; Methodology; Methods; Mining; Molecular Conformation; Molecular Structure; Organism; Plant Viruses; Prevention; Proteins; RNA; RNA Folding; RNA Sequences; RNA Viruses; Research; Resources; Ribosomal RNA; Role; Sampling; Signal Transduction; Structure; Testing; Theoretical model; Time; Transfer RNA; Untranslated RNA; Validation; Viral; Viral Genome; Viral Physiology; Virus; X-Ray Crystallography; algebraic topology; algorithm development; base; chikungunya; combinatorial; experimental study; frontier; insight; interest; mathematical analysis; mathematical model; multimodality; next generation; novel; pathogen; synergism; theories

The most well-studied RNA molecular structures, notably tRNA and rRNA, exist as a single dominant conformation. However, a growing number of small non-coding RNA sequences are known to function by switching between multiple stable configurations. It is expected that such multi modal structural motifs punctuate the ensemble of low-energy structures for an RNA viral genome like Chikungunya, regulating the viral lifecycle. Characterizing these small overlapping sets of stable base pairs, embedded in lengthy sequences with high structural diversity, is essential to understanding how critical structural signals encode the functionality of these important pathogens. This collaboration leverages complementary strengths of previous results --- mining competing signals from the structural ensemble (profiling) and next generation chemical footprinting (SHAPE-MaP) --- to tackle the challenge of multi modal motif discovery in a test set of three alphavirus genomes. This first aim will be achieved by developing the necessary characterizations of profiling landscapes and of SHAPE-MaP signatures to identify target regions with multiple native conformations. These separate results will be validated in individual sequences by the combination of SHAPE-directed profiling, following experimental confirmation of the current prediction methodology. The second aim will demonstrate evolutionary support for these new motifs, first across the three test sequences and then the entire alphaviral family, through a new application of computational algebraic topology. Persistent homology and simplicial complexes will be used to analyze evolution across the different scales at which biological information is encoded in RNA viral genomes, ranging from genomic sequence to vertebrate host. This will be followed by chemical probing confirmation for three additional alphavirus sequences. This project will extend the frontiers of RNA folding by integrating new mathematical models and analyses based on combinatorics and algebraic topology with recent advances in the biochemistry of chemical footprinting for the purposes of identifying significant motifs with multimodal structure in lengthy RNA viral genomes. The results of this study, a set of novel secondary structure motifs in alphavirus genomes which are ideal candidates for further investigation as important functional elements, will be a key resource for RNA virologists. Furthermore, the proposed theoretical and algorithmic developments are generally applicable to all RNA viruses, and hence of significant utility and interest to the scientific community.

研究最充分的RNA分子结构，特别是tRNA和rRNA，以单一优势构象存在。 然而，越来越多的小的非编码RNA序列被认为是通过在不同的基因之间转换来发挥功能的。 多个稳定构型。预计这种多模态结构图案会打断 RNA病毒基因组的低能量结构，如基孔肯雅病毒，调节病毒的生命周期。表征 这些小的重叠的稳定碱基对，嵌入在具有高度结构多样性的长序列中， 这对于理解关键结构信号如何编码这些重要病原体的功能至关重要。 这种合作利用了以前结果的互补优势-从 结构集成（剖析）和下一代化学足迹（SHAPE-地图）-以应对挑战 在三个甲病毒基因组的测试集中发现多模式基序。第一个目标将通过以下方式实现： 对剖面地貌和SHAPE地图特征进行必要的描述，以确定目标 具有多种天然构象的区域。这些单独的结果将在单个序列中由 结合SHAPE-定向剖析，实验证实了目前的预测 方法论第二个目标将证明这些新的基序的进化支持，首先跨越三个 通过计算代数的新应用，测试序列，然后测试整个甲病毒家族 topology.持久同源性和单纯复合物将用于分析不同物种的进化。 生物信息在RNA病毒基因组中编码的尺度，从基因组序列到 脊椎动物宿主随后将对另外三个甲病毒序列进行化学探测确认。 这个项目将通过整合新的数学模型和分析来扩展RNA折叠的前沿 基于组合学和代数拓扑学以及化学足迹生物化学的最新进展 用于鉴定在长RNA病毒基因组中具有多模式结构的重要基序。的 根据这项研究的结果，甲病毒基因组中的一组新的二级结构基序是 作为重要的功能元件，进一步研究将是RNA病毒学家的关键资源。而且 所提出的理论和算法发展通常适用于所有RNA病毒，因此， 对科学界的重要作用和兴趣。