Algorithmic approaches to systems biology, data integration, and evolution

系统生物学、数据集成和进化的算法方法

• 批准号: 10688922
• 负责人: Teresa Przytycka
• 金额: $ 156.78万
• 依托单位: NATIONAL LIBRARY OF MEDICINE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10688922
• 关键词: Acute Renal Failure with Renal Papillary Necrosis; Adult; Affinity; Algorithmic Software; Algorithms; Atlases; Binding; Biological; Biological Process; Cell physiology; Cells; Chemicals; Collaborations; Communities; Complex; Computer Models; Computing Methodologies; DNA; Data; Dependence; Diagnostic; Disease; Drosophila genus; Early Diagnosis; Elements; Environmental Risk Factor; Evolution; Exposure to; Gene Dosage; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Gene Mutation; Generations; Genes; Genetic; Genetic study; Genotype; Goblet Cells; Graph; Growth Factor Gene; Immune response; International; Iowa; Joints; Journals; LCN2 gene; Language; Lead; Legal patent; Link; Machine Learning; Malignant Neoplasms; Methods; Molecular; Mucins; Mutagens; Mutation; National Institute of Diabetes and Digestive and Kidney Diseases; Nature; Network-based; Nucleic Acids; Paper; Pathologic Mutagenesis; Pathway interactions; Pattern; Phenotype; Play; Preparation; Process; Property; Publishing; RNA; Regulatory Element; Reporting; Research; Resolution; Resources; Role; Science; Signal Transduction; Smoking; Specificity; Structure; Structure of parenchyma of lung; System; Systems Biology; Techniques; Technology; Temperature; Tissues; United States National Institutes of Health; Universities; Work; aptamer; base; biological systems; cancer genome; cell type; data integration; design; fly; gene function; graph theory; heterogenous data; insight; large datasets; large scale data; machine learning model; molecular recognition; novel; nuclease; response; sexual dimorphism; theories; tool

Przytycka's group continued to develop and apply computational methods that utilize and integrate large data sets with a focus on gene regulation and diseases. I continued the research on mutation signatures in cancer. Most of the mutations present in cancer genomes are harmless passenger mutations. It has been increasingly appreciated that analyses of the patterns of these mutations can provide useful information regarding mutational processes acting on cancer genomes. Recently we began to leverage the concept mutational signatures to study the relationship of environmental factors, such as smoking and cellular processes in specific tissues. Integrating gene expression and mutational signatures, we examined the relationship of the exposure to smoking and other mutagens with biological processes in healthy tissues, aiming to understand how the exposure to these mutagens impact functioning of cells and tissues. Our preliminary results demonstrated that mutational signatures can be utilized to study the impact of mutagenic environmental factors on molecular pathways and cellular compositions of tissues by allowing a quantification of the strength of these mutagens. The analysis results with this approach are consistent with recent findings linking perturbations of these pathways to smoking but also provided additional novel insights. Our studies indicate that smoking changes expression of many genes and pathways, especially these relater to immune response. It also changes cell type composition in lung tissue increasing the number on mucin producing goblet cells and reducing the number of ciliated cells. Preliminary results of these studies are reported in BioRxiv. A journal submission is in preparation. To gain additional insights into relationships between mutagenic processes and cellular-level changes we developed a network-based approach, GenSigNet, that captures the relations between gene expression and signatures. The construction leverages a sparse partial correlation among other statistical techniques to uncover dominant influence relations between the activities of network nodes. When applied to cancer data, GenSigNet uncovered important connections between mutational signatures and cellular processes that were difficult to detect using previous approaches. Preliminary results of these studies are reported in BioRxiv. A journal submission is in preparation. My group also participates in the international Fly Cell Atlas Consortium that provides a resource for the Drosophila community to study genetic perturbations and diseases at single-cell resolution. The flagship paper of the consortium has been recently published in Science. The single-cell atlas of the entire adult includes 580,000 cells and more than 250 annotated cell types. Together with Brian Oliver's group at NIDDK, my group has lead the analysis of sexual dimorphism. This flagship paper will be followed with further in-depth analyses, including additional analyses of sexual dimorphism co-lead by our two groups. Finally, continuing our long-standing collaboration with Marit Nilsen-Hamilton (Iowa University and Aptalogic), we work on applying computational methods to aid aptamer design. Nucleic acid aptamers are emerging as the new generation molecular recognition elements for diagnostics based on their synthetic nature, stability under a wide range of temperatures and amenability to different sensing platforms. Aptamers can further be modified in sequence and chemically to increase their specificities and affinities for their target molecule and to enhance their stabilities in the presence of nucleases. We filed a joint Aptalogic- NIH patent application for NGAL aptamer. NGAL is an early predictor for acute kidney injury and NGAL aptamer might provide important tool for early detection.

Przytycka的小组继续开发和应用计算方法，该方法利用和整合大型数据集，重点是基因调节和疾病。 我继续研究癌症中突变特征。癌症基因组中存在的大多数突变是无害的乘客突变。越来越多地认为，对这些突变模式的分析可以提供有关作用于癌症基因组的突变过程的有用信息。最近，我们开始利用概念突变特征来研究环境因素的关系，例如吸烟和特定组织中的细胞过程。整合基因表达和突变特征，我们研究了吸烟和其他诱变剂与健康组织中生物过程的关系，旨在了解这些诱变者的暴露如何影响细胞和组织的功能。我们的初步结果表明，可以通过允许对这些诱变剂的强度进行定量来研究诱变环境因素对组织分子途径和细胞组成的影响。使用这种方法的分析结果与将这些途径的扰动联系起来的最新发现是一致的，但也提供了其他新颖的见解。我们的研究表明，吸烟会改变许多基因和途径的表达，尤其是这些基因和途径与免疫反应有关。 它还改变了肺组织中的细胞类型组成，从而增加了产生杯状细胞的粘蛋白数量并减少纤毛细胞的数量。这些研究的初步结果在Biorxiv中报道。期刊提交正在准备。 为了获得对诱变过程与细胞级别变化之间关系的更多见解，我们开发了一种基于网络的方法Gensignet，该方法捕获了基因表达与特征之间的关系。该构建利用了其他统计技术之间的稀疏部分相关性，以发现网络节点活动之间的主要影响关系。当应用于癌症数据时，Gensignet发现了突变特征和细胞过程之间难以检测的重要连接。这些研究的初步结果在Biorxiv中报道。期刊提交正在准备。 我的小组还参加了国际飞池地图集联盟，为果蝇社区提供了以单细胞分辨率研究遗传扰动和疾病的资源。该财团的旗舰文件最近发表在科学上。整个成年人的单细胞地图集包括580,000个细胞和250多个带注释的细胞类型。 我的小组与Niddk的Brian Oliver小组一起领导了性二态性的分析。这份旗舰文件将遵循进一步的深入分析，包括我们两个小组对性二态性共同领导的其他分析。 最后，继续与Marit Nilsen-Hamilton（爱荷华大学和Aptalogic）进行长期合作，我们致力于应用计算方法来帮助适应性设计。 核酸适体基于其合成性，在广泛的温度下的稳定性以及对不同传感平台的稳定性，成为新一代分子识别元素。可以进一步修改适体，并化学化，以增加其目标分子的特异性和亲和力，并在存在核酸酶的情况下增强其稳定性。我们为NGAL适体提交了联合适用性专利申请。 NGAL是急性肾脏损伤的早期预测因子，NGAL适体可能会为早期检测提供重要的工具。