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Maximizing small RNA delivery with signaling pepitdes

通过信号肽最大化小 RNA 递送

基本信息

批准号：
9145216
负责人：
Juliane Nguyen
金额：
$ 23.59万
依托单位：
STATE UNIVERSITY OF NEW YORK AT BUFFALO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-16 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9145216
关键词：
Adverse effects Bacteriophages Biocompatible Materials Biological Assay Biological Availability Biomedical Engineering Carrier Proteins Cell Separation Cells Cellular biology Charge Clinical Code Coupled Cytoplasm Data Development Dose Drug Delivery Systems Formulation Future Gene Silencing Goals Health Immune Lead Libraries Measures Mediating MicroRNAs Molecular Multivesicular Body Nucleic Acids Particle Size Particulate Peptide Signal Sequences Peptides Process Property Protein Engineering Proteins RNA RNA Recognition Motif RNA-Induced Silencing Complex Research Safety Signal Transduction Site Small Interfering RNA Small RNA Sorting - Cell Movement Staging Surface Techniques Testing Therapeutic Treatment Efficacy Virus base cancer cell cell type design health application human disease improved in vivo interdisciplinary approach nanocarrier nanotherapeutic novel protein aminoacid sequence receptor screening trafficking

项目摘要

DESCRIPTION (provided by applicant): The objective of this mechanism-based research is to devise safe and efficient protein particulate nanocarriers (PPC) for small RNA delivery. To accomplish this, we plan to exploit the intracellular trafficking machinery to direct the delivery f small RNAs to their site of action while maximizing small RNA delivery. Small RNAs are used in a range of health applications. However, their potential has yet to be fully realized. This is largely due to inefficient delivery: only 1-2% of small RNAs reach the RNA-induced silencing complex (RISC): the site of action using conventional techniques. Small RNA delivery is a multistep process in which inefficiencies at any stage can compromise the efficacy of gene silencing. In particular, the intracellular fate of synthetic carriers is not well understood and tus poorly controlled. Recent studies indicate that active RISCs are functionally and physically coupled to MVBs and are not free in the cytoplasm as previously thought. Thus, we hypothesize that the effect of small RNA delivery can be significantly increased by actively targeting MVBs. We propose the design of PPCs containing signaling moieties that are recognized by the cell sorting machinery and that serve as "molecular zip codes" for the directed transport of small RNAs to the RISC. This could ultimately lead to enhanced gene silencing. This strategy could improve RNA-based therapy by allowing for the administration of lower doses of therapeutics, thereby reducing side effects and improving safety profiles.

描述（由申请人提供）：这项基于机制的研究的目的是设计用于小RNA递送的安全有效的蛋白质颗粒纳米载体（PPC）。为了实现这一点，我们计划利用细胞内运输机制来引导小RNA递送到它们的作用位点，同时最大化小RNA递送。小RNA用于一系列健康应用。然而，它们的潜力尚未充分发挥。这在很大程度上是由于低效率的递送：只有1-2%的小RNA到达RNA诱导沉默复合物（RISC）：使用常规技术的作用位点。小RNA递送是一个多步骤的过程，其中任何阶段的效率低下都可能损害基因沉默的功效。特别是，合成载体的细胞内命运没有得到很好的理解，并且我们控制得很差。最近的研究表明，活性RISC在功能上和物理上与MVB偶联，并且不像以前认为的那样游离在细胞质中。因此，我们假设小RNA递送的效果可以通过主动靶向MVB而显著增加。我们提出了PPC的设计含有信号传导部分，被细胞分选机识别，并作为“分子邮政编码”的小RNA的直接运输到RISC。这可能最终导致增强的基因沉默。这种策略可以通过允许给予较低剂量的治疗剂来改善基于RNA的治疗，从而减少副作用并改善安全性。