Low-Cost Digital Gene Expression System

低成本数字基因表达系统

• 批准号: 8252104
• 负责人: Steven Jeffrey Gordon
• 金额: $ 78.75万
• 依托单位: INTELLIGENT BIO-SYSTEMS, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8252104
• 关键词: Archives; Base Sequence; Biological Assay; Biological Models; Biology; Biopsy; Blood specimen; Cause of Death; Cell Line; Cells; Clinic; Clinical; Community Healthcare; Complex; DNA; DNA Sequence; Data; Deposition; Development; Disease; ERBB2 gene; Gene Expression; Gene Expression Profiling; Genes; Genome; Genomics; Genotype; Goals; Health Services Research; Histologic; Human; Individual; Knowledge; Lead; Malignant Neoplasms; Malignant neoplasm of prostate; Measures; Medicine; Messenger RNA; Methods; Microarray Analysis; Modeling; Molecular Profiling; Mutation; Nucleotides; Organism; PC3 cell line; Patients; Pharmacogenomics; Phase; Phenotype; Preparation; Price; Process; Progress Reports; Protocols documentation; RNA; Reaction; Reading; Receptor Gene; Regulatory Pathway; Research; Reverse Transcription; Running; Sampling; Sensitivity and Specificity; Sequence Analysis; Solid Neoplasm; Speed; Symptoms; System; Technology; Testing; Therapeutic; Time; Tissues; Tumor Subtype; base; cancer diagnosis; cancer therapy; clinical decision-making; cost; cost effectiveness; digital; erbB-2 Receptor; innovation; instrument; leukemia/lymphoma; malignant breast neoplasm; neoplastic; next generation; peripheral blood; repository; tool; treatment strategy; tumor

DESCRIPTION (provided by applicant): As the second most common cause of death in the US, cancer is caused by random mutations in an organism's genome. Although precise knowledge of the genomic sequence within neoplastic tissues can be an indicator for treatment, for example the erbB-2 receptor gene (Her-2) for breast cancer, such correlations are few and often do not adequately define tumor subtypes important in therapeutic decisions. Such inability to identify a subclass of tumors which may not respond to standard therapies can restrict the development of more efficacious treatment strategies. The analysis of gene expression represents an indirect measure of the genetic alterations in tumors through the analysis of regulatory pathways. Microarray technologies have proven to be powerful tools and offer the promise of better clinical decision-making based on tumor phenotypes. Highly promising preliminary studies of leukemia, lymphomas, and solid neoplasms demonstrate that gene expression data can highlight differences between otherwise histologically identical diseases. However, microarray-based technologies are limited in their ability to analyze low expression levels. We use of a unique sequencing by synthesis technology as a digital gene expression system to obtain precise counts of expressed mRNA molecules. This can provide an order of magnitude more sensitivity than microarray systems. In this Phase II project, we will build upon the sample preparation protocols developed in Phase I and use these with an extremely low-cost, proprietary, next-generation sequencing system that can perform the sequencing required for a gene expression study for about $100 or about 1/20th the price of the most competitive sequencing method. PUBLIC HEALTH RELEVANCE: Ultimately, the ability to produce very inexpensive gene expression and detailed DNA sequence information related to cancer will lead for a much wider use of expression and sequence analyses for research and treatment of this devastating disease. In addition, the ability to analyze complex organisms' genomes at a very low cost will both lead to accelerated discoveries throughout biology and provide the basis for Pharmacogenomics, a new paradigm in therapeutics wherein medicines are prescribed based on individual genotypes rather than just observed symptoms.

描述（由申请人提供）：作为美国第二大常见死因，癌症是由生物体基因组中的随机突变引起的。虽然肿瘤组织内基因组序列的精确知识可以是治疗的指标，例如乳腺癌的erbB-2受体基因（Her-2），但这种相关性很少，并且通常不能充分定义在治疗决策中重要的肿瘤亚型。这种无法识别可能对标准疗法无反应的肿瘤亚类的能力可能会限制更有效治疗策略的开发。基因表达的分析代表了通过分析调控途径对肿瘤中遗传改变的间接测量。微阵列技术已被证明是强大的工具，并提供了更好的临床决策的基础上肿瘤表型的承诺。对白血病、淋巴瘤和实体瘤的非常有希望的初步研究表明，基因表达数据可以突出组织学上相同的疾病之间的差异。然而，基于微阵列的技术在其分析低表达水平的能力方面是有限的。我们使用独特的合成测序技术作为数字基因表达系统，以获得表达的mRNA分子的精确计数。这可以提供比微阵列系统高一个数量级的灵敏度。在这个第二阶段项目中，我们将建立在第一阶段开发的样品制备方案的基础上，并将其与一个成本极低的、专有的下一代测序系统一起使用，该系统可以以大约100美元或最具竞争力的测序方法价格的1/20的价格进行基因表达研究所需的测序。 公共卫生关系：最终，产生与癌症相关的非常便宜的基因表达和详细的DNA序列信息的能力将导致表达和序列分析在这种毁灭性疾病的研究和治疗中的更广泛的应用。此外，以非常低的成本分析复杂生物体基因组的能力将加速整个生物学的发现，并为药物基因组学提供基础，药物基因组学是治疗学的一种新范式，其中药物是基于个体基因型而不仅仅是观察到的症状。