Automated and sensitive genomic co-profiling for precision pharmacogenomics

用于精准药物基因组学的自动化、灵敏的基因组共同分析

基本信息

批准号：
9303306
负责人：
Paul Clark Blainey
金额：
$ 13.15万
依托单位：
BROAD INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-24 至 2017-08-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9303306
关键词：
Address Affect Autoimmune Process Biology Biomass CD4 Positive T Lymphocytes Cells Chemicals Chemistry Chromatin Clinic Clinical Medicine Complex Computational Biology Computer Simulation Data Development Disease Drug Prescriptions Etiology Gene Expression Genes Genomic medicine Genomics Histone Deacetylase Histone Deacetylase Inhibitor Human Human Genome Immunity Infection Inflammatory Libraries Link Maps Measurement Mentored Research Scientist Development Award Methods Microfluidic Microchips Microfluidics Molecular Profiling Neurologic Process Nucleic Acids Patients Performance Peripheral Blood Mononuclear Cell Persons Pharmaceutical Preparations Pharmacogenomics Pilot Projects Positioning Attribute Preparation Process Reporting Research Personnel Running Safety Sampling System T-Lymphocyte Techniques Technology Testing Therapeutic Therapeutic Effect Time Training Translating Ursidae Family Valproic Acid Vorinostat computerized tools design epigenome epigenomics experience genome sequencing genomic profiles inhibitor/antagonist microbial microdevice novel novel drug class personalized medicine pleiotropism polarized cell prevent response transcription factor transcriptome transcriptome sequencing tubacin

项目摘要

Project Summary/Abstract Genomics methods like expression profiling and epigenomic profiling hold enormous potential benefit to parse the effects of drugs and assess patient response to therapy in the clinic. However, the lack of advanced sample preparation methods is a blocking issue in translating informative genomic techniques for application in chemical biology and clinical medicine. Even advanced single-cell genomics methods require large total input quantities and struggle to produce more than one type of genomic profile, which may not be sufficiently informative or predictive. Powerful computational tools to integrate multiple layers of `omic information are available and ready to accept data if available from the right samples. Thus, the need to prepare multiple sequence library types at the same time (eg co-profiling epigenome and transcriptome) from small numbers of primary cells in a single streamlined system is a crucial missing link in the advancement of chemical biology and realizing the potential impact of genomic medicine. The proposed project will solve this sample preparation challenge by establishing simultaneous epigenomic and expression co-profiling sample preparation method from low biomass samples in an automated microfluidic device. The co-profiling sample preparation system will constitute a single microdevice able to accept small multiple primary cell samples and automatically produce multiple sequence library types in a single run. We will apply this capability to dissect the pleiotropic effects of an important new drug class, histone deacetylase inhibitors (HDACi). HDACi have (currently) unpredictable effects on gene activity, but show promise for therapeutic modulation of proliferative, inflammatory, autoimmune, and neurological processes. To evaluate potential therapeutic effects and safety (regarding immunity to infection) of HDACi treatment, we will co-profile HDACi-treated human primary cells.

项目概要/摘要表达谱和表观基因组谱等基因组学方法具有巨大的潜在优势可供解析药物的作用并评估患者对临床治疗的反应。但缺乏先进的样品制备方法是将信息丰富的基因组技术转化为应用的一个障碍问题化学生物学和临床医学。即使是先进的单细胞基因组学方法也需要大量的总输入数量并努力产生不止一种类型的基因组图谱，这可能还不够信息性或预测性。整合多层“组学信息”的强大计算工具是如果可以从正确的样本中获得数据，则可用并准备好接受数据。因此，需要准备多个同时从少量的序列文库类型（例如共同分析表观基因组和转录组）单一流线型系统中的原代细胞是化学生物学进步中至关重要的缺失环节并认识到基因组医学的潜在影响。拟议的项目将解决这个示例通过同时建立表观基因组和表达联合分析样本来制备挑战在自动化微流体装置中从低生物量样品制备方法。共同分析样本制备系统将构成一个能够接受少量多个原代细胞样品的单个微型装置，在一次运行中自动生成多种序列库类型。我们将应用此功能来剖析一种重要的新药——组蛋白脱乙酰酶抑制剂（HDACi）的多效性作用。 HDACi 有（目前）对基因活性的影响不可预测，但显示出对增殖、炎症、自身免疫和神经系统过程。评估潜在的治疗效果和安全性（关于感染免疫力）HDACi 治疗，我们将共同分析 HDACi 处理的人类原代细胞。