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Nucleic Acid Nanostructures and their Cellular Transport Mechanisms

核酸纳米结构及其细胞运输机制

基本信息

批准号：
1710105
负责人：
Nathan Gianneschi
金额：
$ 42万
依托单位：
University of California-San Diego
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-01 至 2018-02-28
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1710105&HistoricalAwards=false
关键词：
Nucleic Acid Nanostructures their Cellular

项目摘要

Non-TechnicalMolecules and materials used in medical applications make intimate contact with our cells and tissues. This is true for pharmaceuticals commonly administered to patients, through to metal implants used in reconstructive surgery. These contacts between manmade materials and natural, biological systems are poorly understood, and difficult to probe and optimize. For example, medicines can have off-target effects, and implants can cause unwanted rejection or scarring. These interfaces must be better understood and optimized to correctly target tissues for better therapies. This project will develop new strategies for understanding how materials interact with cells. Specifically, to find fundamentally new methods for delivering gene based therapeutics to diseased tissues. Students will be exposed to a grand challenge in medicine, biology, materials science and chemistry, while working specifically on advanced polymers and biochemical screening techniques applicable to the study of many types of systems. Through interdisciplinary collaborations, the team seeks to impact both the field of biomaterials broadly, but also highlight the positive outcomes of working outside of normally well defined fields of study to bring different ways of approaching hard problems together in the lab to effect change. TechnicalGianneschi and coworkers have developed nanoparticles that serve to protect DNA from enzymatic degradation while facilitating cellular entry and are able to modulate mRNA levels in live human cells with no appreciable toxicity. This development represents a significant advancement towards non-toxic nucleic acid delivery systems that can be synthesized by simple protocols. However, as with many other biologically active nanomaterials, the mechanisms underlying, cellular uptake, endosome escape, mRNA regulation and nuclease resistance are not understood. This project's goal is to develop a universally applicable method that will allow researchers to understand the mechanisms involved in nanomaterial uptake by cells. This will also enable identification of potential bottlenecks that are associated with nanomaterial function and facilitate optimization of materials for downstream applications. Through a combination of advanced gene-editing tools and materials synthesis, new uptake pathways will be discovered, optimized, and then utilized to modulate gene expression allowing several routes towards treatment of disease including the sensitization of cells to therapies to which they are otherwise resistant. The proposed work is a fundamental biomaterials investigation of new structures, and new biological interfaces.

医疗应用中使用的非技术分子和材料与我们的细胞和组织密切接触。对于通常用于患者的药物，到用于重建手术的金属植入物，情况都是如此。人们对人造材料和自然生物系统之间的这些联系知之甚少，也很难对其进行探索和优化。例如，药物可能会产生非靶向效应，植入物可能会导致不想要的排斥反应或疤痕。必须更好地理解和优化这些接口，以便正确地针对组织进行更好的治疗。该项目将开发新的策略，以了解材料如何与细胞相互作用。具体地说，找到从根本上为疾病组织提供基于基因的疗法的新方法。学生将接触到医学、生物学、材料科学和化学方面的重大挑战，同时专门研究适用于许多类型系统研究的先进聚合物和生化筛选技术。通过跨学科合作，该团队寻求对生物材料领域产生广泛影响，但也强调了在通常定义良好的研究领域之外开展工作的积极成果，将实验室内解决难题的不同方法结合在一起，以实现变革。技术Gianneschi和他的同事已经开发出纳米颗粒，这种纳米颗粒可以保护DNA免受酶降解，同时促进细胞进入，并且能够调节活的人类细胞中的mRNA水平，而没有明显的毒性。这一进展代表着朝着可通过简单方案合成的无毒核酸递送系统的方向迈进了一大步。然而，与许多其他具有生物活性的纳米材料一样，其潜在的机制，如细胞摄取、内小体逃逸、mRNA调控和核酸酶抵抗等尚不清楚。该项目的目标是开发一种普遍适用的方法，使研究人员能够了解细胞摄取纳米材料的机制。这也将有助于识别与纳米材料功能相关的潜在瓶颈，并促进下游应用的材料优化。通过先进的基因编辑工具和材料合成的结合，新的吸收途径将被发现、优化，然后被用来调节基因表达，从而允许几种治疗疾病的途径，包括使细胞对其他疗法敏感。建议的工作是对新结构和新生物界面的基础生物材料的研究。