UNM COBRE: THEORETICAL STUDY OF SPECIFICITY OF RNA SILENCING MECHANISM

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。RNA干扰（RNA interference, RNAi）过程是最近发现的一种细胞机制，在基因水平的免疫应答和基因调控中起着关键作用。RNAi目前在制药和生物界引起的巨大兴奋源于其广泛的潜在治疗应用，包括治疗癌症、艾滋病毒、高血压、黄斑变性、亨廷顿氏病和无数其他严重疾病。此外，RNAi似乎是基因组研究中前所未有的强大工具，正在引领新一代的基因科学。尽管RNAi取得了明显的成功，并引起了人们的高度兴奋，但要将这一过程转变为可靠、稳健和安全的技术，仍有许多关键的开放性问题必须得到回答。特别是，我们需要改进RNAi疗效的预测模型，更好的非特异性（“脱靶”或“假阳性”）效应的模型和控制，RNAi调控系统的网络模型，以及设计基于RNAi的敲除的信息支持工具。大愿景是整个RNAi途径的生化过程及其与基因组编码和非编码部分的相互作用的完整模型。我的研究小组正在朝着这一愿景开展一些研究方向，包括siRNA功效预测、脱靶分析、基因家族敲低设计和高性能字符串分析算法（以支持前面的方向）。我们的研究结果包括提高对RNAi生物学的理解，使RNAi从业者能够更好地预测和控制RNAi干预结果的模型和算法，以及实现这些模型的一套公开可用的软件工具。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The RNA interference (RNAi) process is a recently discovered cellular mechanism that plays key roles in genetic-level immune response and genetic regulation. The immense excitement that RNAi is currently arousing in the pharmaceutical and biology communities stems from its wide spectrum of potential therapeutic applications including the treatment of cancer, HIV, high blood pressure, macular degeneration, Huntington's disease, and a myriad of other serious ailments. Further, RNAi appears to be an unprecedently powerful tool for genomic research that is ushering in a new generation of genetic science. In spite of the visible successes of RNAi, and the high level of excitement surrounding it, there are a number of critical open questions that must be answered to transition this process into a reliable, robust, and safe technology. In particular, we need improved predictive models of RNAi efficacy, better models of and controls for nonspecific ("off-target" or "false positive") effects, network models of the RNAi regulatory system, and informatic support tools for designing RNAi-based knockdowns. The grand vision is a complete model of the biochemical processes of the whole RNAi pathway and its interaction with coding and non-coding sections of the genome. My research group is working on a number of research directions toward this vision, including siRNA efficacy prediction, off-target analysis, gene family knockdown design, and high performance string analysis algorithms (to support the previous directions). The results of our studies include improved understanding of the biology of RNAi, models and algorithms that allow RNAi practitioners to better predict and control the results of RNAi interventions, and a suite of publicly available software tools that implement these models.