Collaborative Research: CDI-Type II: Probing Complex Dynamics of Small Interfering RNA (siRNA) Transfection by Petascale Simulations and Network Analysis

双链RNA介导的RNA干扰基因沉默的发现是生物和生物医学科学中最令人兴奋的最新进展之一。RNAi利用双链小干扰RNA(SiRNA)靶向并破坏真核细胞中互补的mRNA来调节基因表达。自从十多年前发现siRNA以来，科学家们已经研究了基于siRNA的许多疾病的潜在用途，如癌症、肝炎、人乳头瘤病毒和高胆固醇血症。原则上，siRNA比其他类型的药物具有更广泛的治疗应用，因为siRNA可以被人工设计成通过RNAi机制使任何基因沉默。因此，治疗应用的主要挑战是高效、无毒地将siRNA递送到感兴趣组织内的细胞。CDI项目的研究目标是通过超级计算机模拟来设计高效的siRNA递送系统。通过数百万个原子的模拟研究：(1)siRNAs对脂膜分子结构的影响以及结构变化如何影响膜的通透性；(2)附着在金纳米颗粒上的siRNA分子通过膜进入细胞的分子机制；(3)通过超声波传递脂质体中的siRNAs。计算技术将被用于实现高效siRNA递送系统的自动化设计。该项目旨在促进学生在学术和专业方面的卓越表现。已经建立了一个双学位项目，让学生有机会获得物理科学或工程学科的博士学位，以及计算机科学的硕士学位，专门从事高性能计算和模拟。该研究小组还将为来自历史上黑人学院和大学以及少数民族服务机构的本科生和教师导师组织计算科学研讨会。

The discovery of RNA interference mediated gene silencing by double-stranded RNA is one of the most exciting recent developments in the biological and biomedical sciences. RNAi utilizes a pathway whereby a double-stranded small interfering RNA (siRNA) targets and destroys complementary mRNA in eukaryotic cells to regulate gene expression. Since its discovery just over a decade ago scientists have investigated the potential use of siRNA-based treatment of many diseases such as cancer, liver cirrhosis, hepatitis B, human papillomavirus, and hypercholesterolemia. In principle, siRNA has much broader therapeutic applications than other types of drugs because siRNA can be synthetically designed to silence any gene via the RNAi machinery. Therefore, the primary challenge for therapeutic applications is efficient and non-toxic delivery of siRNA to cells within tissues of interest. The research goal of this CDI project is to design efficient delivery systems for siRNA via supercomputer simulations. Multimillion-atom simulations are performed to study: (1) the effect of siRNAs on the molecular structure of lipid membranes and how structural changes affect the membrane permeability; (2) molecular mechanisms by which siRNA molecules attached to gold nanoparticles cross the membrane and go into a cell; and (3) delivery of siRNAs encapsulated in liposomes by ultrasound. Computational technologies will be used to enable automated design of efficient siRNA delivery systems. This project is promoting scholastic and professional excellence among students. A dual-degree program has been established which gives students the opportunity to obtain a Ph.D. in the physical sciences or an engineering discipline and an M.S. in computer science with specialization in high performance computing and simulations. This research team will also organize computational science workshops for undergraduate students and faculty mentors from Historically Black Colleges and Universities and Minority Serving Institutions.