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（通过应用程序提供）：基于机制的研究的目的是设计安全有效的蛋白质特异性纳米载体（PPC）来递送小RNA。为此，我们计划探索细胞内贩运机制，以将小RNA的交付f带到其动作部位，同时最大程度地提高小型RNA的交付。小型RNA用于一系列健康应用中。但是，它们的潜力尚未完全实现。这很大，由于递送无效：只有1-2％的小RNA到达RNA诱导的沉默复合物（RISC）：使用常规技术的作用部位。小型RNA递送是一个多步过程，在任何阶段，无效的能力都会损害基因沉默的有效性。特别是，合成载体的细胞内命运尚未得到充分理解，而tu的控制不佳。最近的研究表明，主动RISC在功能和物理上与MVBS耦合，并且在细胞质中并非如前所述。这是我们假设，通过主动靶向MVB，可以显着提高小RNA递送的影响。我们提出了包含由细胞分类机械识别的信号部分的PPC的设计，并用作“分子邮政编码”，用于将小RNA的定向运输到RISC上。这最终可能导致增强的基因沉默。该策略可以通过允许较低剂量的治疗来改善基于RNA的治疗，从而减少副作用并改善安全性。