Identification and Analysis of Lipid-Like Materials for Nucleic Acid Delivery

描述(由申请人提供)：该项目致力于推进核酸疗法领域，这可能会通过改变有问题的基因靶点的表达，对人类疾病的治疗和预防产生变革性的影响。具体地说，这项研究将试图通过对类脂递送载体(我们称之为类脂)的研究，来解决与无毒递送DNA和siRNA相关的挑战。这项建议的总体目标包括：1.开发使用类脂纳米粒安全有效地输送核酸的高质量候选物。2.探索基于类脂的递送的潜在机制，以便能够有洞察力地设计未来几代类脂递送剂。这些一般目标将首先通过高通量化学合成大量新的和多样化的类脂纳米粒来实现。将对这些类脂进行筛选，以确定它们是否能够以无毒的方式将核酸运送到HeLa细胞。领先的候选者将进一步接受动物治疗潜力的测试。最后，为了能够改进未来类脂递送载体文库的设计，我们将尝试深入了解类脂递送机制。这将通过使用荧光粒子跟踪的运输研究以及旨在确定类脂结构-功能关系的分子建模研究来实现。我们期待这样的实验将带来令人兴奋的新材料，能够进行特定的基因操作，以及更好地理解类脂蛋白的功能。一旦克服了与交付相关的挑战，核酸疗法有可能给疾病治疗和预防领域带来革命性的变化。这项研究将研究由类脂材料制成的纳米颗粒安全有效地传递siRNA和DNA的能力，同时深入了解传递作用的机制。

DESCRIPTION (provided by applicant): This project sets out to advance the field of nucleic acid therapeutics, which is likely to have a transformative effect on the treatment and prevention of human disease through the altered expression of problematic gene targets. Specifically, this study will attempt to address the challenges associated with the non-toxic delivery of DNA and siRNA through the investigation of lipid-like delivery vehicles (which we term 'lipidoids'). The general objectives of this proposal include: 1. Development of high-quality candidates for the safe and effective delivery of nucleic acids using lipidoid delivery nanoparticles. 2. Exploration of the underlying mechanisms of lipidoid-based delivery in order to enable the insightful design of future generations of lipidoid delivery agents. These general objectives will be accomplished first through the high throughput chemical synthesis of a large library of new and diverse lipidoid nanoparticles. These lipidoids will be screened for their ability to deliver nucleic acids to HeLa cells in a non-toxic fashion. Leading candidates will be further examined for therapeutic potential in animals. Finally, in order to enable the improved design of future libraries of lipidoid delivery vehicles, we will attempt to gain insight into lipidoid delivery mechanisms. This will be accomplished through transport studies using fluorescent particle tracking as well as molecular modeling studies intended to identify structure-function relationships for lipidoids. We expect that such experiments will lead to exciting new materials capable of specific gene manipulation as well as a better understanding of lipidoid function. Nucleic acid therapeutics has the potential to revolutionize the field of disease treatment and prevention once the challenges associated with delivery are overcome. This study will investigate the ability of nanoparticles made from lipid-like materials to safely and effectively deliver siRNA and DNA while gaining insight into the mechanisms of delivery action.