A novel approach for reversal of autophagic defects using lysosome-targeted nanoparticles

使用溶酶体靶向纳米颗粒逆转自噬缺陷的新方法

基本信息

  • 批准号:
    9914192
  • 负责人:
  • 金额:
    $ 20.06万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-04-15 至 2022-02-28
  • 项目状态:
    已结题

项目摘要

ABSTRACT Ample data support a role for impaired lysosomal acidification and reduced autophagic flux in comorbidities related to obesity, including non-alcoholic fatty liver disease (NAFLD), heart failure, and impaired insulin secretion in diabetes. Investigation of the role of impaired lysosomal acidification in the pathophysiology of NAFLD, heart failure, and diabetes has been hampered by the lack of a technology to acidify lysosomes. To facilitate mechanistic studies of acutely restoring lysosomal pH, we recently published that photoactivated release of acid from lysosome-targeted nanoparticles (NPs) provides immediate short-term restoration of optimal pH and autophagic flux. However, to translate such technology for long-term acidification and for in vivo use, there is a need to develop NPs that release acid independent of an external trigger. This proposal stems from our development of novel formulations that allow lysosome-targeted NPs to sense their entry into the lysosomes and then trigger the release of acid. To this end, we capitalized on the observation that impaired acidification, documented in various diseases, only elevates the pH by 0.6-1 units. Therefore, the pH of the dysfunctional lysosome is still significantly more acidic than the cytosol and plasma. Consequently, we designed a new NP formulation that releases acid at pH 6 and below to assure that acid release will only occur in the lysosome. We hypothesize that acid-activated-acid-release NPs (acNPs) will allow for continuous treatment and long-term restoration of lysosomal acidity and autophagic flux. In this study we will develop, test, and validate acNP in cultured cells. Our long term goal is to develop the acNPs to be used in vivo. Preliminary data show that the acNPs efficiently target lysosomes. Furthermore, preliminary data in a hepatocyte cell line demonstrate the capacity of the acNPs to restore pH and autophagic flux under conditions of impaired lysosomal function induced by chronic exposure to excess lipids. To address our hypothesis we propose the following two aims: Aim1: Synthesize and characterize lysosome targeted acNPs that activate at pH 6 where we will test the hypothesis that lysosome targeted acNPs enter the cells through endocytosis and follow them through their maturation into the lysosome, where at pH ≤6 they will trigger acid release and restore lysosomal pH and autophagic flux. And Aim 2: Determine the capacity of acNPs to enable long-term restoration of autophagic flux under conditions that impair lysosomal acidification where we will test the hypothesis that in cells treated with excess lipid environment, re-acidification of lysosomes by acNP will restore autophagic flux, mitochondrial turnover, and cellular functions including insulin sensitivity in the hepatocyte and insulin secretion in the beta cell.
摘要

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Modulating lysosomal pH: a molecular and nanoscale materials design perspective.
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MARK W. GRINSTAFF其他文献

MARK W. GRINSTAFF的其他文献

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{{ truncateString('MARK W. GRINSTAFF', 18)}}的其他基金

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R21:一种用于治疗鳞状细胞肺癌的新型抗体药物偶联物
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    10510002
  • 财政年份:
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    $ 20.06万
  • 项目类别:
R21: A novel antibody-drug conjugate for treatment of squamous cell lung carcinoma
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    $ 20.06万
  • 项目类别:
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缓释松弛素2治疗肩周炎
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生物材料转化研究
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  • 财政年份:
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  • 资助金额:
    $ 20.06万
  • 项目类别:
A novel approach for reversal of autophagic defects using lysosome-targeted nanoparticles
使用溶酶体靶向纳米颗粒逆转自噬缺陷的新方法
  • 批准号:
    9752911
  • 财政年份:
    2019
  • 资助金额:
    $ 20.06万
  • 项目类别:
R21: Acidic Nanoparticles for Restoration of Autophagy in Age-associated NAFLD
R21:酸性纳米颗粒用于恢复年龄相关性 NAFLD 中的自噬
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    2019
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    $ 20.06万
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Dissolvable Hydrogel Dressing for the Treatment of Burns
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  • 项目类别:

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