Single Somatic Cell Epigenetic Models

单体细胞表观遗传模型

基本信息

批准号：
8904246
负责人：
Mark T Muller
金额：
$ 31.82万
依托单位：
TOPOGEN, INC.
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-05 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8904246
关键词：
Acute Address Aging Algorithms Animal Model Animals Area Binding Bioinformatics Biological Assay Biological Models Biomedical Research Businesses Cell Cycle Cell Line Cell Maintenance Cell Nucleus Cell division Cell model Cells Chronic Chronic Disease Clinical Medicine Complement Complex Country Cytosine DNA DNA Methylation DNA Modification Process DNA Repair DNA Sequence Alteration DNA-Binding Proteins Data Defect Development Diagnostics Research Disease Disease model Economics Engineering Epigenetic Process Event Evolution FDA approved Failure Fluorochrome Future Future Generations Gene Expression Gene Silencing Gene Silencing Pathway Generations Genes Goals Grant Growth Health Histones Homeostasis Homing Human Human Pathology Image In Vitro Industry Inflammatory Inflammatory Bowel Diseases Inheritance Patterns Knowledge Life Link Maintenance Malignant Neoplasms Marketing Mediating Medical Economics Metabolic Diseases Methylation Methyltransferase MicroRNAs Modeling Monitor Mutagens Mutation Natural Product Drug Neurologic New Agents New Territories Nuclear Nucleosides Occupations Organism Parkinson Disease Pathway interactions Performance Pharmaceutical Preparations Pharmacologic Substance Phase Phenotype Physiological Process Protein Isoforms Proteins Protocols documentation Public Health Publishing Reagent Regulation Reporter Research Research Personnel Resolution Role Route S Phase Series Small Business Innovation Research Grant Solid Somatic Cell Specificity Stem cells Sum System Technology Therapeutic Time Tissues Toxic effect Translating Tumor Suppressor Genes Validation aging nutrition base cancer cell cancer therapy cellular imaging cost design drug discovery encryption endonuclease epigenome epigenomics expression vector flexibility human disease imprint in vivo innovation insight killings nervous system disorder nonhuman primate novel novel strategies novel therapeutics personalized medicine prototype repaired research and development research study screening small molecule targeted cancer therapy trait treatment strategy uptake

项目摘要

DESCRIPTION (provided by applicant): Epigenetic modifications of DNA and histones are stable encryption systems essential for life. For example, the importance of DNA methylation is underscored by the consequences of its mis-regulation, which include defects in tissue homeostasis, chronic disease and accelerated aging; thus epigenetics broadly impacts human health. The information stored in the distribution of 5-methyl-cytosine is flexible, stable and heritable after cell division; however, unlike genetic mutation, epigenetic changes may be pharmacologically reversed. The goal of this research is to commercialize products that will be used to develop a better understanding of the evolution of epigenetic miscues in disease and to discover new epi-therapuetics. We propose a series of fluorochrome- based reporter kits with content rich protocols that examine epigenetic reprogramming (imprinting) and DNA methylation maintenance in human disease. Such products will see applications in discovery of treatment strategies in cancer, Parkinson's disease, Inflammatory Bowel Disease, as well as developing an understanding behind the newly discovered epigenomic clock (aging) in human and non-human primates. This will promote new therapeutic inroads by identifying druggable targets, and dissecting pathway proteins regulating DNA methylation aging and chronic disease. The commercial products are based on a model system that uses endogenous GFP/RFP reporters and homing endonuclease mediated damage-repair by homologous and non- homologous routes; both pathways induce methylation revision at repaired DNA segments and yield new epialleles. Because this is a cell based imprinting, two important benefits will be realized. First high resolution, single cell epigenetics will be possible; and second, a single cell can be tracked into future generations by live imaging. The company will offer a selection of reporters (expression vectors, ad hoc engineered cell lines and kits) to examine alterations in methylation revisions and repair in defined disease models. This will allow an innovative screening system for novel epi- therapeutics in a cellular context. In sum, this proposal translates the basic information on DNA methylation maintenance into a flexible system that can be used to monitor, manipulate and dissect the process in somatic cells and animal models. These products will be used in diverse areas of biomedical research (studies on environmental connectivity to epigenetic circuitry, neurologic, inflammatory, metabolic diseases, epigenetic mutagens, chronic multi-trait diseases, nutrition, aging, etc). For the Phase II SBIR a new bioinformatic algorithm i described that interprets epiallele evolution for application in clinical and personalized medicine

描述（由申请人提供）：DNA 和组蛋白的表观遗传修饰是生命所必需的稳定加密系统，例如，DNA 甲基化的重要性因其错误调节的后果而凸显，其中包括组织稳态缺陷、慢性疾病和疾病。加速衰老；因此表观遗传学广泛影响人类健康，但与基因突变不同，5-甲基胞嘧啶分布中存储的信息是灵活、稳定和可遗传的。这项研究的目标是将产品商业化，用于更好地了解疾病中表观遗传错误的进化，并发现新的表观治疗药物。我们提出了一系列内容丰富的基于荧光染料的报告试剂盒。检查人类疾病中的表观遗传重编程（印记）和 DNA 甲基化维持的方案将应用于发现癌症、帕金森病、炎症性肠病的治疗策略，以及开发一种新的治疗方法。了解人类和非人类灵长类动物中新发现的表观基因组时钟（衰老），这将通过识别可药物靶点并剖析调节 DNA 甲基化衰老和慢性疾病的途径蛋白来促进新的治疗进展。使用内源性 GFP/RFP 产生和归巢核酸内切酶通过同源和非同源途径介导的损伤修复；两种途径均诱导修复的 DNA 片段甲基化修正并产生新的表观等位基因。这是基于细胞的印记，将实现两个重要的好处：第一，可以实现高分辨率的单细胞表观遗传学；第二，可以跟踪单个细胞。该公司将提供一系列生产者（表达载体、特设工程细胞系和试剂盒）来检查特定疾病模型中甲基化修正和修复的变化，这将为新型表观遗传疾病的创新筛选系统提供支持。总之，该提案将 DNA 甲基化维持的基本信息转化为一个灵活的系统，可用于监测、操纵和剖析体细胞和动物模型中的过程。的领域生物医学研究（研究表观遗传回路、神经系统、炎症、代谢疾病、表观遗传诱变剂、慢性多性状疾病、营养、衰老等的环境连通性）。在临床和个体化医学中的应用