Synthesis and Applications of Chemically-Modified Oligonucleotides

Nucleic 核酸是构成生物大分子DNA和RNA的主要成分 具有巨大的生物学功能。 例如，核酸包含细胞的遗传蓝图，将这种遗传密码转移到信使RNA是指导独特蛋白质合成所必需的。 核酸还具有其他生物学功能，包括控制特定基因的表达。 以来 自65年前发现DNA双螺旋结构以来， 在核酸领域的重大进展，以改善其性质， 生物技术应用或现代医学。 例如，基因沉默寡核苷酸是用于了解基因功能的工具。然而，由于这些分子的天然结构，限制继续存在。利用有机化学，我的研究计划开发合成类似物， 来改善它的生物学功能。 然后我的研究小组评估这些生物学影响， 合成类似物。 我的研究小组的主要重点是合成小说 化学修饰的寡核苷酸用作基因沉默寡核苷酸。 首先，我们将探讨在一个类内扩大小分子的影响 基因沉默分子称为短干扰RNA（siRNA）。我的实验室已经确定了siRNAs中的一个区域，可以进行各种化学修饰。因此，我们将扩大范围和地点 这些分子可以直接与不同的细胞生物成分相互作用。当结合时，这些分子可能表现出改善的效力、细胞膜渗透性和稳定性。 第二、 我们将扩大siRNA内光响应基团的范围。 我们的实验室已经证明， 分子偶氮苯，当置于siRNA的核心中心区域内时， 用于可逆地控制基因沉默活性的时间。 偶氮苯可以在反式和 分别在可见光和紫外光存在下形成顺式。 我们将扩大光敏范围 RNA组，并探讨siRNA内的功能化偶氮苯衍生物。这将使我们能够微调活动 的siRNA，使我们能够更好地控制其活性，从而防止 脱靶效应 最后我 研究小组在开发新的骨架修饰方面具有专业知识， 寡核苷酸我们将扩大 这些修改的范围，并探索它们在CRISPR（定期间隔聚类）中的效果 短回文重复序列）/Cas9编辑系统。的 CRISPR/Cas9系统是一个令人兴奋的，相对较新的系统， 在各种生物系统中表现出顺从性。 多学科 实验室工作由本科生和研究生组成的优秀团队进行 学生谁使用相结合的溶液，固相和生物 技术.因此，受训人员 在我的实验室监督下，他们为各种职业做好了充分的准备， 专注于化学和科学的职业。

Nucleic acids are the main building blocks of DNA and RNA, which are biomacromolecules with vast biological function. For example, nucleic acids contain the genetic blue print of the cell, and transfer of this genetic code to messenger RNA is necessary to direct the synthesis of unique proteins. Nucleic acids also have other biological functions including controlling the expression of particular genes. Since the discovery of the double helical structure of DNA 65 years ago, there have been significant advances in the nucleic acid field to improve its properties for biotechnological applications or for modern medicine. For instance, gene-silencing oligonucleotides are tools used to understand gene function. However, limitations continue due to the native structure of these molecules. Using organic chemistry, my research program develops synthetic analogs in order to improve its biological function. My research group then evaluates the biological impact of these synthetic analogs. The primary focus of my research group involves synthesizing novel chemically-modified oligonucleotides to use as gene-silencing oligonucleotides. First, we will explore the effect of expanding small molecules within a class of gene silencing molecules called short interfering RNAs (siRNAs). My lab has identified an area within siRNAs that is amenable to diverse chemical modification. As such, we will expand the scope and place molecules that can interact directly with different cellular biological components. When bound, these molecules may exhibit improved potency, cell-membrane permeability, and stability. Secondly, we will expand the scope of photoresponsive groups within siRNAs. Our lab has shown that the photoresponsive molecule, azobenzene, when placed within the core central region of siRNAs can be used to reversibly control the timing of gene silencing activity. Azobenzene can isomerize between a trans and cis form in the presence of visible and ultra-violet light, respectively. We will expand the scope of photoresponsive RNA groups, and explore functionalized azobenzene derivatives within siRNAs. This will allow us to fine-tune the activity of siRNAs, and allow us to better control its activity, and thus prevent off-target effects. Finally, my research group has expertise in developing novel backbone modifications for oligonucleotides. We will expand the scope of these modifications and explore their effect within the CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 editing system. The CRISPR/Cas9 system is an exciting, and relatively new system that has been shown to be amenable within a variety of biological systems. The multidisciplinary laboratory work is conducted by a talented team of undergraduate and graduate students who use a combination of solution-phase, solid-phase and biological techniques. As such, the trainees supervised from my lab are well prepared for a variety of professions including careers focused in chemistry and science.