Protein Misfolding Diseases and Oxido-Reductive Pathways

蛋白质错误折叠疾病和氧化还原途径

基本信息

  • 批准号:
    7938819
  • 负责人:
  • 金额:
    $ 75.21万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-09-30 至 2014-07-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION Abstract Certain inherited modes of heart failure and several neurodegenerative diseases are characterized by protein misfolding states whose underlying mechanism(s) and pathophysiology are poorly understood. Effective therapies exist primarily as goals, not as clinical implementations. Macromolecular damage induced by oxidative stress is the sine qua non for thinking about many diseases. Our laboratory has challenged this paradigm by demonstrating that mouse hearts exhibiting protein-folding cardiomyopathy found in humans are under 'reductive stress' from an over-active antioxidative system. Decreasing the function of glucose-6-phosphate dehydrogenase (G6PD), which generates the reductant NADPH, "cures" the disease in mice by ameliorating reductive stress, aggresome formation, hypertrophy, heart failure and death. This experiment defines a novel causal mechanism and implicates G6PD as a potential therapeutic target. We hypothesize that stress response and anti-oxidative pathways undergo a pathogenic transition, and become dysregulated by macromolecular stresses (e.g., misfolded proteins). We further propose that other cardiac and neurodegenerative diseases result from similar pathogenic transition. Our Pioneer Award proposal is designed to develop a robust experimental platform for exploring the mechanisms of reductive stress disease. Our work will extend from studies that model reductive stress in the genetically amenable fruit fly Drosophila melanogaster, through cultured mouse and human cells, to whole mice, and finally into patients as we work to develop diagnostic tools. Cuttingedge imaging techniques will be developed for monitoring redox couples and toxicities in living cells and tissues. Genetic screens in Drosophila will guide the identification of new genes and determine the effects of potentially therapeutic compounds that prevent reductive stress disease. Validation in mice of interacting genes and pathways will provide us target candidates for pharmacolog
描述

项目成果

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Ivor James Benjamin其他文献

Ivor James Benjamin的其他文献

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{{ truncateString('Ivor James Benjamin', 18)}}的其他基金

Advancing Student Potential for Inclusion with Research Experiences (ASPIRE)
通过研究经验提升学生融入的潜力(ASPIRE)
  • 批准号:
    10678356
  • 财政年份:
    2023
  • 资助金额:
    $ 75.21万
  • 项目类别:
Training in Signature Transdisciplinary Cardiovascular Sciences
标志性跨学科心血管科学培训
  • 批准号:
    10198992
  • 财政年份:
    2017
  • 资助金额:
    $ 75.21万
  • 项目类别:
Training in Signature Transdisciplinary Cardiovascular Sciences
标志性跨学科心血管科学培训
  • 批准号:
    10628014
  • 财政年份:
    2017
  • 资助金额:
    $ 75.21万
  • 项目类别:
Training in Signature Transdisciplinary Cardiovascular Sciences
标志性跨学科心血管科学培训
  • 批准号:
    9209572
  • 财政年份:
    2017
  • 资助金额:
    $ 75.21万
  • 项目类别:
Training in Signature Transdisciplinary Cardiovascular Sciences
标志性跨学科心血管科学培训
  • 批准号:
    9914120
  • 财政年份:
    2017
  • 资助金额:
    $ 75.21万
  • 项目类别:
Conditional HSF1 Expression for Ischemic Cardioprotection
条件性 HSF1 表达对缺血性心脏保护作用
  • 批准号:
    7689421
  • 财政年份:
    2009
  • 资助金额:
    $ 75.21万
  • 项目类别:
Conditional HSF1 Expression for Ischemic Cardioprotection
条件性 HSF1 表达对缺血性心脏保护作用
  • 批准号:
    7786189
  • 财政年份:
    2009
  • 资助金额:
    $ 75.21万
  • 项目类别:
Conditional HSF1 Expression for Ischemic Cardioprotection
条件性 HSF1 表达对缺血性心脏保护作用
  • 批准号:
    8195885
  • 财政年份:
    2009
  • 资助金额:
    $ 75.21万
  • 项目类别:
Protein Misfolding Diseases and Oxido-Reductive Pathways
蛋白质错误折叠疾病和氧化还原途径
  • 批准号:
    8143267
  • 财政年份:
    2009
  • 资助金额:
    $ 75.21万
  • 项目类别:
Protein Misfolding Diseases and Oxido-Reductive Pathways
蛋白质错误折叠疾病和氧化还原途径
  • 批准号:
    8537969
  • 财政年份:
    2009
  • 资助金额:
    $ 75.21万
  • 项目类别:

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