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（由申请人提供）：人类基因组项目提供了一个无与伦比的机会，可以促进我们对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，还包括控制控制生物体及其身体部位发展的遗传调节网络（GRN）。这份共享的仪器赠款（SIG）专门针对后一种挑战，它要求关键的高吞吐量DNA测序能力为一个积极地在再生生物学的最前沿的跨学科科学家组的用户组。所要求的基因组分析仪II非常适合支持现在开始作为该财团工作的一部分的广泛的鼠尾草和芯片序列分析。主要用户正在追求三个主要依赖提议的仪器的主要项目，他们还是NIH NIH跨学科研究联盟的主要研究人员和联合研究人员，这是2007年秋天NIH授予的九项此类U54赠款之一。可以从关于自然如何建立器官的内源性发展中确定的基本遗传信息，以遗传调节网络（GRN）的形式确定。反过来，这些信息可用于制造从干细胞的器官零件来修复器官损伤并替换器官损耗。 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人类和老鼠。这些大数据集将集​​成在计算水平上，以构建基因调节网络（GRN），该基因调节网络可以由组织工程师使用，以建造三个器官零件，即牙齿胚芽，胰岛和心脏瓣膜。这些器官部分体现了共同的发育原理，但代表了不同的结构，生理和机械终点。高吞吐量DNA测序仪器对于需要这种潜在基因组数据的联盟项目和整个财团的成功至关重要。因此，我们要求Illumina Genome Analyzer II以实现综合RNA谱（使用SAGE库）和转录因子-DNA相互作用（使用CHIP-SEQ）的全基因组图。最后，为了进一步确保这种有价值的工具的最佳利用并将其收益扩展到更广泛的社区，我们已将有才华的其他用户招募到我们的用户群体中，并为我们的用户组提供了令人信服的项目。 公共卫生相关性：基因组科学的进步使假设以遗传调节网络的形式可以从内源性的发展中确定有关自然如何建立器官的形式的基本遗传信息。可以通过要求的高吞吐量DNA测序仪获得此信息，可用于制造器官零件以修复器官损坏。我们的长期目标是构建一个“分子蓝图”，其中包含基因调节网络和其他信息以构建三个器官：（1）牙齿胚芽，以取代牙齿脱落并提供可易易的模型系统，以快速临床翻译； （2）用于治疗I型糖尿病的胰岛细胞； （3）心脏流出阀，为瓣膜心脏病提供长期治疗，这是儿童死亡和成人发病率的主要原因。