Global Discovery and Validation of Functional Regulatory Elements

描述（由申请人提供）：了解人类基因组中的调控元件是我们理解复杂生物和疾病系统的关键一步。调控因素比基因更难识别，而且可能比基因中实际的编码差异更能解释个体之间的差异。识别和研究包括启动子、增强子、沉默子和绝缘子在内的元件，将随着复杂的调控网络的揭示而产生新的治疗策略。到目前为止，真正功能调控元件的表征和验证一直是一个低通量的努力，因为每个调控位点都被克隆到报告基因分析和测试中。本提案提出了一种新的方法，通过将其与创新的分选和测序系统相结合，以高通量的方式执行最常见的验证分析之一，瞬时转染。该系统已被证明是实用和可行的，将允许快速和彻底地识别整个人类基因组中调控元件的作用方法。候选人在计算机科学和分子生物学方面的背景从本科到研究生和博士后工作提供了一个完整的背景，应该允许在博士后环境中实施和扩展所描述的实验。科学的性质和产生的数据应该允许作为一个新的教员继续和扩展工作。斯坦福大学和斯奈德实验室提供了一个优秀的环境，为候选人的发展和过渡到长期的独立研究生涯做准备。作为该计划的一部分，候选人将通过在线课程结合指导委员会和继续教育。该计划的两个阶段的最终结果将是科学成果，这些成果可以扩展到有用和重要的医学和科学相关领域，因为它们与人类表达的调节有关。所描述的创新方法将允许候选人在本资助计划结束后继续从事各种各样的工作。反过来，候选人将在项目结束时被定位为独立的主要研究者和有价值的合作者。

DESCRIPTION (provided by applicant): Understanding of regulatory elements in the human genome is a key step in our ability to understand complex biological and disease systems. Regulatory elements are much more difficult to identify than genes and likely account for more variation among individuals than actual coding differences in genes. Identifying and studying elements, including promoters, enhancers, silencers, and insulators, will lead to new therapeutic strategies as the complex regulatory networks are revealed. Up to now the characterization and validation of truly functional regulatory elements has been a low throughput endeavor as each regulatory site is cloned into a reporter assay and tested. This proposal produces a novel method that performs one of the most common validation assays, transient transfections, in a high-throughput manner by combining it with an innovative sorting and sequencing system. This system, which has been shown to be practical and feasible, will allow for rapid and thorough identification of the method of action of regulatory elements throughout the human genome. The candidate's background in both computer science and molecular biology ranging from undergraduate to graduate school and post-doctoral work provides a complete background that should allow for implementation and extension of the described experiment in the post-doctoral environment. The nature of the science and the data produced should allow continuation and extension of the work as a new faculty member. Stanford and the Snyder lab provide an outstanding environment for a strong program allowing development of the candidate and preparation for transition to a long-term independent research career. As part of this program, the candidate will combine a mentoring committee with continuing education via available online courses. The end result of both phases of the program will be scientific results that can be extended into useful and important medically and scientifically relevant areas as they relate to regulation of expression in humans. The innovative methods described will allow the candidate to pursue various lines of endeavor well past the end of this funding program. In turn the candidate will be positioned at the end of the program to function as an independent principle investigator and valuable collaborator.