Self-replicating RNA-nanoplexes for programming monocytes to regenerate the heart

用于编程单核细胞以再生心脏的自我复制RNA纳米复合物

基本信息

  • 批准号:
    8968584
  • 负责人:
  • 金额:
    $ 23.6万
  • 依托单位:
  • 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:
    2015-07-15 至 2017-06-30
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION: There are currently no treatments capable of restoring cardiac function after myocardial infarction (MI) besides cardiac transplantation. MI kills millions of heart cells due to reduced oxygen and blood supply. Strategies to regenerate damaged heart cells that use proteins, such as neuregulin (NRG1), to stimulate mitosis of surviving cardiomyocytes could partially restore infarcted myocardium. However, delivering such therapeutics to the heart using conventional methods is difficult for two reasons: (1) heart blood vessels show very low permeability for large molecules, (2) molecules that do reach the heart are washed away rapidly by the high blood flow. In clinical studies, NRG1's short half-life necessitates daily systemic injections. Further, the fraction that reaches the heart is very low, compromising its therapeutic efficacy. This non-targeted approach can also lead to the uncontrolled proliferation of cardiomyocytes in the remote zone of the heart, causing myocardial hyperplasia and hypertrophy. Clearly there is an urgent need for a non-invasive and controlled delivery approach that can specifically target surviving cardiomyocytes in the infarcted area and border zone. We propose to develop a novel delivery strategy that fulfills this need. Our approach will target infarcted cardiac tissue by exploiting the body's immunological response to MI. Specifically, we propose to deliver regenerating proteins using monocytes that naturally migrate to the site of infarction. Monocytes show extraordinary retention in the heart in spite of high blood flow due to specific receptor-ligand interactions with the extracellular matrix and other proteins. We hypothesize that (1) monocytes can be targeted and genetically programmed with self-replicating RNA-nanoplexes to express NRG1 and that (2) monocytes will home to infarcted tissue and locally release NRG1, a protein that can induce cardiomyocyte proliferation and facilitate tissue regeneration. To test these hypotheses, we will first generate self-replicating RNA-nanoplexes that target monocytes and program them to express NRG1. Secondly, we will quantify the number of MI-homing monocytes that are genetically programmed for protein production in a mouse model of MI. We anticipate that these studies will lead to a living drug reservoir that is non-invasive and able to locally deliver protein therapeutics to the infarcted sie and its border zone. This has profound implications for the treatment of patients with IHD and the regeneration of infarcted myocardium.


项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(1)

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Juliane Nguyen其他文献

Juliane Nguyen的其他文献

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{{ truncateString('Juliane Nguyen', 18)}}的其他基金

Developing genetically encodable probes for multimodal tracking of exosomal RNA cargo
开发用于外泌体 RNA 货物多模式追踪的基因可编码探针
  • 批准号:
    10681827
  • 财政年份:
    2023
  • 资助金额:
    $ 23.6万
  • 项目类别:
Engineering a cross-linked cellular network for cardiac repair
设计用于心脏修复的交联细胞网络
  • 批准号:
    10539723
  • 财政年份:
    2022
  • 资助金额:
    $ 23.6万
  • 项目类别:
Polarizing Macrophages to Tumor Suppressors by Blocking Multiple CCR2 Chemokine Receptor Epitopes
通过阻断多个 CCR2 趋化因子受体表位将巨噬细胞极化为肿瘤抑制因子
  • 批准号:
    10380283
  • 财政年份:
    2021
  • 资助金额:
    $ 23.6万
  • 项目类别:
Polarizing Macrophages to Tumor Suppressors by Blocking Multiple CCR2 Chemokine Receptor Epitopes
通过阻断多个 CCR2 趋化因子受体表位将巨噬细胞极化为肿瘤抑制因子
  • 批准号:
    10328882
  • 财政年份:
    2020
  • 资助金额:
    $ 23.6万
  • 项目类别:
Polarizing Macrophages to Tumor Suppressors by Blocking Multiple CCR2 Chemokine Receptor Epitopes
通过阻断多个 CCR2 趋化因子受体表位将巨噬细胞极化为肿瘤抑制因子
  • 批准号:
    9973323
  • 财政年份:
    2020
  • 资助金额:
    $ 23.6万
  • 项目类别:
Polarizing Macrophages to Tumor Suppressors by Blocking Multiple CCR2 Chemokine Receptor Epitopes
通过阻断多个 CCR2 趋化因子受体表位将巨噬细胞极化为肿瘤抑制因子
  • 批准号:
    10737843
  • 财政年份:
    2020
  • 资助金额:
    $ 23.6万
  • 项目类别:
Polarizing Macrophages to Tumor Suppressors by Blocking Multiple CCR2 Chemokine Receptor Epitopes
通过阻断多个 CCR2 趋化因子受体表位将巨噬细胞极化为肿瘤抑制因子
  • 批准号:
    10524148
  • 财政年份:
    2020
  • 资助金额:
    $ 23.6万
  • 项目类别:
Polarizing Macrophages to Tumor Suppressors by Blocking Multiple CCR2 Chemokine Receptor Epitopes
通过阻断多个 CCR2 趋化因子受体表位将巨噬细胞极化为肿瘤抑制因子
  • 批准号:
    10559551
  • 财政年份:
    2020
  • 资助金额:
    $ 23.6万
  • 项目类别:
Self-replicating RNA-nanoplexes for programming monocytes to regenerate the heart
用于编程单核细胞以再生心脏的自我复制RNA纳米复合物
  • 批准号:
    9105404
  • 财政年份:
    2015
  • 资助金额:
    $ 23.6万
  • 项目类别:
Maximizing small RNA delivery with signaling pepitdes
通过信号肽最大化小 RNA 递送
  • 批准号:
    9145216
  • 财政年份:
    2015
  • 资助金额:
    $ 23.6万
  • 项目类别:

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