Modulation of lysosomal function for the treatment of Batten disease

调节溶酶体功能治疗巴顿病

基本信息

  • 批准号:
    9976592
  • 负责人:
  • 金额:
    --
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-09-30 至 2020-08-02
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY/ABSTRACT Neuronal ceroid lipofuscinoses (NCLs or Batten disease) are among the most devastating inherited disorders of childhood and the most common cause of neurodegeneration in children in the U.S. There is currently no cure for these disorders, and treatments remain largely supportive. NCLs are characterized by the progressive intralysosomal accumulation of undegraded cellular material; this accumulation is thought to result from defects in the autophagy-lysosomal pathway, but could itself contribute to pathogenesis. Our data show that deficiency of the juvenile Batten disease protein, CLN3, impairs maturation of a subset of lysosomal enzymes and that trehalose-mediated activation of TFEB, a master regulator of the autophagy-lysosomal pathway, ameliorates disease burden in a mouse model of juvenile Batten disease (JNCL). We propose to study novel mechanisms of TFEB activation that could lead to translational applications for JNCL and other neurodegenerative disorders caused by defects in lysosome-mediated cellular clearance. First, we will test the hypothesis that trehalose- induced lysosomal enhancement corrects defective maturation of lysosomal enzymes in JNCL mice (Aim 1). We will test this hypothesis by conducting experiments of protein maturation and by unbiased proteomic analyses based on the use of a knock-in Lamp1FLAG mouse line we have generated to efficiently isolate lysosomes from mouse tissues. Second, we will test the hypothesis that reduction or inhibition of Akt, a kinase inhibitor of TFEB we have identified, will decrease neuropathology of JNCL mice (Aim 2). We will reduce Akt activity by using two complementary approaches: genetically, by using Akt1-/- mice, and pharmacologically, by using an Akt drug inhibitor that is currently in clinical development. Third, we will test the hypothesis that synergistic pharmacological activation of TFEB by modulation of two orthogonal pathways will result in a greater enhancement of the autophagy-lysosomal system and better reduction of JNCL pathological hallmarks than either strategy alone (Aim 3). This hypothesis is based on our finding that the non-receptor tyrosine kinase, Src, is an essential factor for activation of mTORC1, another kinase inhibitor of TFEB. These studies will pioneer pharmacological activation of TFEB in a model of neurodegenerative disorder. If successful, this study will provide a powerful paradigm of TFEB activation that could lay the foundation for the clinical treatment of Batten disease and, potentially, additional neurodegenerative storage disorders caused by impairment of the autophagy-lysosomal pathway.
项目总结/文摘

项目成果

期刊论文数量(0)
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Marco Sardiello其他文献

Marco Sardiello的其他文献

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{{ truncateString('Marco Sardiello', 18)}}的其他基金

TFEB-mediated lysosome-to-nucleus signaling in aging and lifespan regulation
TFEB 介导的溶酶体到细胞核信号传导在衰老和寿命调节中的作用
  • 批准号:
    10172235
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
TFEB-mediated lysosome-to-nucleus signaling in aging and lifespan regulation
TFEB 介导的溶酶体到细胞核信号传导在衰老和寿命调节中的作用
  • 批准号:
    10413974
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
TFEB-mediated lysosome-to-nucleus signaling in aging and lifespan regulation
TFEB 介导的溶酶体到细胞核信号传导在衰老和寿命调节中的作用
  • 批准号:
    10583543
  • 财政年份:
    2021
  • 资助金额:
    --
  • 项目类别:
Mechanisms Of Er-To-Golgi Transport Of Lysosomal Enzymes
溶酶体酶从 Er 到高尔基体的转运机制
  • 批准号:
    10345430
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Mechanisms Of Er-To-Golgi Transport Of Lysosomal Enzymes
溶酶体酶从 Er 到高尔基体的转运机制
  • 批准号:
    10376728
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Mechanisms Of Er-To-Golgi Transport Of Lysosomal Enzymes
溶酶体酶从 Er 到高尔基体的转运机制
  • 批准号:
    10094001
  • 财政年份:
    2019
  • 资助金额:
    --
  • 项目类别:
Modulation of lysosomal function for the treatment of neuronal ceroid lipofuscino
调节溶酶体功能治疗神经元蜡样脂褐质
  • 批准号:
    9103210
  • 财政年份:
    2012
  • 资助金额:
    --
  • 项目类别:
Modulation of lysosomal function for the treatment of Batten disease
调节溶酶体功能治疗巴顿病
  • 批准号:
    10317363
  • 财政年份:
    2012
  • 资助金额:
    --
  • 项目类别:
Modulation of lysosomal function for the treatment of Batten disease
调节溶酶体功能治疗巴顿病
  • 批准号:
    10247068
  • 财政年份:
    2012
  • 资助金额:
    --
  • 项目类别:
Modulation of lysosomal function for the treatment of neuronal ceroid lipofuscino
调节溶酶体功能治疗神经元蜡样脂褐质
  • 批准号:
    8458325
  • 财政年份:
    2012
  • 资助金额:
    --
  • 项目类别:

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