Information flow and state transitions at the system and multi-dimensional scales in leukemia progression

白血病进展中系统和多维尺度的信息流和状态转换

• 批准号: 10392361
• 负责人: YA-HUEI KUO
• 金额: $ 86.32万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10392361
• 关键词: 1q22; Acute Myelocytic Leukemia; Behavior; Biological; Biological Process; CBFbeta-MYH11 fusion protein; Cancer Biology; Cells; Chromosomal Rearrangement; Clinic; Collection; Communities; Complex; DNA; DNA Methylation; DNA Sequence Alteration; Data; Development; Disease; Disease Progression; Epigenetic Process; Event; Evolution; Explosion; Gene Expression Profile; Genes; Genome; Genomics; Goals; Health; Hematopoiesis; Human; Immune system; Institution; Lead; Leukemic Cell; Malignant - descriptor; Malignant Neoplasms; Maps; Mathematics; Measures; Messenger RNA; Methylation; MicroRNAs; Modeling; Modification; Mutation; Oncogenic; Onset of illness; Pathogenesis; Pathway interactions; Patients; Potential Energy; Probability; Process; Published Comment; RNA; Relapse; Research; Rest; Sampling; Series; System; Systems Biology; Time; Transgenes; Untranslated RNA; Work; base; biobank; cancer cell; cancer therapy; clinical phenotype; combinatorial; design; epigenome; experimental study; fusion gene; genome-wide; genomic data; geometric methodologies; high dimensionality; information model; insight; leukemia; mathematical methods; mathematical model; mathematical theory; mouse model; new therapeutic target; novel; peripheral blood; personalized medicine; predicting response; targeted treatment; theories; tool; transcriptome; treatment response; tumor progression

PROJECT SUMMARY Cancer begins as a disease of the genome, with DNA mutations initiating a cascade of events that lead to cancer progression. As single or small collection of cells undergo state transitions to become cancer cells and ultimately evolve into a malignant neoplasm, the immune system is activated and new vasculature is formed, involving non-cancerous cells in the system. This process involves the flow and transfer of information across multiple scales in time and space. Information is encoded within and transferred between cells and across multiple genomic scales may be detected at the system’s level. Our hypothesis is that information contained in one or multiple genomic landscapes can be used to detect oncogenic perturbations and predict response to therapy. It has been shown that mutations associated with AML can be detected years before the onset of disease, however, they do not predict when the disease will manifest or response to treatment. Nevertheless, these sets of mutations can be characterized by distinct gene expression signatures collectively representing perturbations underlying the observed clinical phenotypes. Thus, there is an urgent need for novel and insightful interrogations and predictions of high-dimensional genomic data sets on a system level. Our approach aims to 1) make use of the maximum amount of relevant information in the system 2) be simple and parsimonious with the data, and 3) provide insight and predictions. We propose to validate a mathematical model and approach that considers genome-wide gene activity as state transition from a healthy state to a cancer state from the perspectives of messenger RNAs (mRNAs; transcriptome), non-coding microRNA (miRNAs; the miRome), and DNA methylation (epigenome). The theory and mathematics of state transitions is well known in the systems biology community and is a powerful tool for interpreting and predicting the behavior of complex systems such as genomics and cancer biology. The central hypothesis of this proposal is that information produced during a biological process such as cancer, can be detected from different viewpoints (i.e., transcriptome, miRome, epigenome) such that information contained in one viewpoint of the genomic landscape can be mapped into another, and that disease development and progression can be interpreted and predicted with mathematical models of information flow in a multidimensional genomic space. We propose the following aims: Specific Aim 1. Parameterize a mathematical model of multi-dimensional state transition. Specific Aim 2. Quantify the impact of treatment on state transition dynamics and develop a model of therapy response and relapse. We will quantify and model therapy response in controlled AML mouse model. Specific Aim 3. Characterize the information contained in the transcriptome, miRome, and epigenome state-spaces. Impact. Through an iterative dialog between biological experiments and mathematical modeling, this work will provide insight into perturbations contributing to leukemia initiation and progression, which will guide the design of new therapies targeting pathways at critical transition points.

项目概要 癌症始于基因组疾病，DNA 突变引发一系列导致癌症的事件 单个或一小部分细胞经历状态转变，最终成为癌细胞。 进化成恶性肿瘤，免疫系统被激活，新的血管系统形成，涉及 该过程涉及多个细胞之间的信息流动和传递。 信息在时间和空间上进行编码并在细胞之间以及跨多个细胞进行传输。 我们的假设是，基因组尺度可以在系统水平上检测到。 多个基因组景观可用于检测致癌扰动并预测对治疗的反应。 研究表明，与 AML 相关的突变可以在疾病发作前数年被检测到， 然而，他们并不能预测疾病何时显现或对治疗的反应。 突变的特征可以通过共同代表扰动的不同基因表达特征来表征 因此，迫切需要新颖且富有洞察力的询问。 我们的方法旨在 1）利用系统级别的高维基因组数据集。 系统中相关信息的最大量 2) 数据简单且简洁，3) 我们建议验证考虑的数学模型和方法。 从健康状态到癌症状态的状态转变的全基因组基因活动 信使 RNA（mRNA；转录组）、非编码 microRNA（miRNA；miRome）和 DNA 甲基化 （表观基因组）状态转换的理论和数学在系统生物学界众所周知。 是解释和预测复杂系统（例如基因组学和 该提案的中心假设是生物过程中产生的信息。 例如癌症，可以从不同的角度（即转录组、miRome、表观基因组）进行检测，以便 基因组景观的一个观点中包含的信息可以映射到另一个观点中，并且该疾病 发展和进步可以用信息流的数学模型来解释和预测 我们提出以下目标： 具体目标 1. 参数化 a 多维状态转换的数学模型 具体目标 2. 量化治疗对的影响。 我们将量化和建模状态转换动力学并开发治疗反应和复发的模型。 受控 AML 小鼠模型中的治疗反应 具体目标 3. 描述中包含的信息。 转录组、miRome 和表观基因组状态空间之间的迭代对话。 生物实验和数学建模，这项工作将提供对扰动的深入了解 白血病的发生和进展，这将指导针对关键通路的新疗法的设计 过渡点。