High Throughput Genome Sequencer for Organ Building

用于器官构建的高通量基因组测序仪

• 批准号: 7598886
• 负责人: RICHARD L MAAS
• 金额: $ 49.87万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-27 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7598886
• 关键词: Address; Adult; Award; Biological Models; Biology; Body part; Cardiac; Cessation of life; Childhood; Clinical; Communities; Complex; DNA; DNA Sequence; Data; Data Set; Development; Disease; Ensure; Gene Expression; Genetic; Genetic Variation; Genome; Genomics; Goals; Grant; Heart Valve Diseases; Heart Valves; Human; Human Genome Project; In Vitro; Insulin-Dependent Diabetes Mellitus; Interdisciplinary Study; Islet Cell; Islets of Langerhans; Location; Maps; Mechanics; Molecular; Morbidity - disease rate; Mus; Nature; Organ; Organism; Physiological; Principal Investigator; RNA; Regulator Genes; SAGE Library; Science; Scientist; Stem cells; System; Tissue Engineering; Tooth Germ; Tooth Loss; Translations; United States National Institutes of Health; Work; base; engineering design; falls; genome-wide; instrument; instrumentation; public health relevance; regenerative; repaired; success; transcription factor

DESCRIPTION (provided by applicant): The Human Genome Project affords an unrivaled opportunity to advance our understanding of the genetic basis of organismal biology. The potential impact of genomic sequence information includes not only understanding the contribution of genetic variation to complex disease, but also discovery of the genetic regulatory networks (GRNs) that control the development of organisms and their body parts. This shared instrumentation grant (SIG) specifically addresses this latter challenge, by requesting key high throughput DNA sequencing capability for a user group of interdisciplinary scientists who are actively working at the forefront of regenerative biology. The Genome Analyzer II requested is ideally suited to support the extensive SAGE and ChIP-Seq analyses now commencing as part of this Consortium effort. The Major Users are pursuing three major projects that rely critically on the proposed instrumentation, and they are also Principal Investigators and co-Principal Investigators on an NIH Interdisciplinary Research Consortium, one of nine such U54 grants awarded by the NIH in the fall of 2007. The central premise of the Systems-Based Consortium for Organ Design and Engineering, or SysCODE (http://www.SysCODE.org), is that fundamental genetic information, in the form of genetic regulatory networks (GRNs), can be determined from endogenous development about how nature builds organs. This information, in turn, can be used to fabricate organ parts from stem cells to repair organ damage and replace organ loss. A major challenge facing this Consortium is to acquire and use genomic data sets representing: (1) temporally dynamic and spatially defined gene expression data (e.g., SAGE) from both endogenous organ development and in vitro stem cell systems induced to differentiate to specific organ fates, and (2) genome wide location data (e.g., ChIP-Seq) for key transcription factors that are either necessary or sufficient for organ development, as proven by mutational analysis in humans and mice. These large data sets will be integrated at the computational level to construct gene regulatory networks (GRNs) that can be used by tissue engineers to build three organ parts, the tooth germ, the pancreatic islet, and the heart valve. These organ parts embody common developmental principles, but represent distinct structural, physiologic and mechanical endpoints. High throughput DNA sequencing instrumentation will be essential to the success of the Consortium projects that require this underlying genomic data, and to the success of the Consortium as a whole. We are therefore requesting the Illumina Genome Analyzer II to enable the construction of comprehensive RNA profiles (using SAGE libraries) and genome-wide maps of transcription factor-DNA interactions (using ChIP-Seq). Lastly, to further ensure optimal use of this valuable instrument and to extend its benefits to a broader community, we have enlisted a talented set of Other Users with scientifically compelling projects to our user group. PUBLIC HEALTH RELEVANCE: Advances in genome science make possible to postulate that fundamental genetic information, in the form of genetic regulatory networks, can be determined from endogenous development about how nature builds organs. This information, which can be obtained via the high throughput DNA sequencer being requested, can be used to fabricate organ parts to repair organ damage. Our long term goal is to construct a "molecular blueprint" that contains gene regulatory network and other information to build three organ parts: (1) the tooth germ, to replace tooth loss and provide a tractable model system for rapid clinical translation; (2) pancreatic islet cells, for treatment of Type I diabetes; and (3) cardiac outflow valves, to provide a long- term therapy for valvular heart disease, a major cause of childhood death and adult morbidity.

描述（申请人提供）：人类基因组计划提供了一个无与伦比的机会，以促进我们对生物体生物学遗传基础的理解。基因组序列信息的潜在影响不仅包括了解遗传变异对复杂疾病的贡献，还包括发现控制生物体及其身体部位发育的遗传调控网络（GRNs）。这个共享仪器补助金（SIG）专门解决了后一个挑战，通过为活跃在再生生物学前沿的跨学科科学家的用户组请求关键的高通量DNA测序能力。所要求的基因组分析仪II非常适合支持广泛的SAGE和ChIP-Seq分析，目前正在开始作为该联盟工作的一部分。主要用户正在进行三个主要项目，这些项目严重依赖于拟议的仪器，他们也是NIH跨学科研究联盟的主要研究者和共同主要研究者，这是NIH在2007年秋季授予的九个U 54赠款之一。器官设计与工程系统联盟（Systems-Based Consortium for Organ Design and Engineering，简称SysCODE）（http：//www.example.com）的核心前提是，基本的遗传信息，以遗传调控网络（GRN）的形式，可以从关于自然如何构建器官的内源性发展中确定。www.SysCODE.org反过来，这些信息可以用来从干细胞中制造器官部件，以修复器官损伤和替代器官损失。该联盟面临的一个主要挑战是获取和使用代表以下的基因组数据集：（1）时间动态和空间定义的基因表达数据（例如，SAGE），以及（2）基因组范围的位置数据（例如，ChIP-Seq）的关键转录因子，这是必要的或足够的器官发育，如在人类和小鼠的突变分析证明。这些大型数据集将在计算水平上进行整合，以构建基因调控网络（GRNs），组织工程师可以使用该网络构建三个器官部分，即牙胚、胰岛和心脏瓣膜。这些器官部分体现了共同的发育原则，但代表了不同的结构，生理和机械终点。高通量DNA测序仪器对于需要这种基础基因组数据的联盟项目的成功以及整个联盟的成功至关重要。因此，我们要求Illumina Genome Analyzer II能够构建全面的RNA图谱（使用SAGE文库）和转录因子-DNA相互作用的全基因组图谱（使用ChIP-Seq）。最后，为了进一步确保最佳利用这一宝贵的工具，并将其好处扩展到更广泛的社区，我们已经招募了一批有才华的其他用户，他们为我们的用户群提供了科学上令人信服的项目。 公共卫生相关性：基因组科学的进步使人们有可能假设，基本的遗传信息，以遗传调控网络的形式，可以从内源性发展确定自然如何建立器官。该信息可以通过所请求的高通量DNA测序仪获得，可以用于制造器官部件以修复器官损伤。我们的长期目标是构建一个包含基因调控网络和其他信息的“分子蓝图”，以构建三个器官部分：（1）牙胚，以替代牙齿缺失并为快速临床翻译提供易于处理的模型系统;（2）胰岛细胞，用于治疗I型糖尿病;以及（3）心脏流出瓣膜，为心脏瓣膜病提供长期治疗，心脏瓣膜病是儿童死亡和成人发病的主要原因。