Role of mTORC1 in Retinal Ganglion Cell Physiology and Disease

mTORC1 在视网膜神经节细胞生理和疾病中的作用

基本信息

  • 批准号:
    10673155
  • 负责人:
  • 金额:
    $ 52.21万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-09-01 至 2024-07-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY This work addresses a fundamental knowledge gap in our understanding of retinal physiology and function that has significant bearing on the early effects of diabetes on the neural retina. Mechanistic target of rapamycin (mTOR) kinase forms the core of two multi-protein complexes: mTOR complex 1 (mTORC1) containing the protein Raptor, and mTORC2 complex containing the protein Rictor. The mTOR signaling network is essential for cellular responses to trophic signals, control of cell metabolism, protein synthesis, cell growth and cell motility. Numerous studies show a key role for mTOR complexes in neuronal function, including axon guidance, dendrite arborization and synaptic plasticity; and numerous neurological disorders are associated with dysfunctions of the mTOR signaling pathway. In contrast, knowledge of the roles of mTOR complexes in retinal physiology and disease is very limited. We propose to test a distinct cell-specific role for mTORC1 in normal retinal ganglion cell (RGC) physiology and to determine if loss of mTORC1 activity is a key contributor to loss of RGC function and viability in diabetes. The proposed study is based on our prior findings that diabetes causes progressive loss of total retinal protein synthesis (Fort, P.E. et al. 2014, Diabetes 63(9):3077-90) and preliminary data showing that: 1) mouse RGC exhibit a high rate of protein synthesis that is dependent upon mTORC1 function, and 2) negating mTORC1 function in the inner retina caused eventual loss of RGC, similar to the neurodegeneration causes by diabetes. mTORC1 activity is required for 5' cap- dependent translation of mRNAs encoding the protein-synthetic machinery. Thus, in Specific Aim 1 we plan to examine the role of mTORC1 activity in RGC protein synthesis and maintenance of RGC function and viability. We will test the hypothesis that loss of mTORC1 function in RGC inhibits translation of a discrete set of mRNAs, eventually leading to a decrease in the general protein synthetic capacity, visual function and viability of RGC. The proposal is also based upon the premise that diabetes causes stress and damage to the neural retina, and RGC in particular. Deactivation of mTORC1 decreases 5' cap-dependent protein translation in response to a number of cellular stresses. Preliminary data also show that diabetes diminishes RGC protein synthesis coinciding with increased expression of the stress-responsive inhibitor of mTORC1 called regulated in development and DNA damage (REDD1). Thus, in Specific Aim 2 we plan to determine if the effects of diabetes on RGC mRNA translation, function and viability are due to lack of mTORC1 activity leading to a reduction in protein synthesis capacity. We will test the hypothesis that maintaining mTORC1 activity and RGC protein translation during diabetes prevents RGC loss and dysfunction. Defining the role of mTORC1 in RGC will greatly increase our knowledge of RGC physiology and of the ways in which diabetes affects the neural retina.
项目总结

项目成果

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Steven F Abcouwer其他文献

Steven F Abcouwer的其他文献

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{{ truncateString('Steven F Abcouwer', 18)}}的其他基金

Role of mTORC1 in Retinal Ganglion Cell Physiology and Disease
mTORC1 在视网膜神经节细胞生理和疾病中的作用
  • 批准号:
    10458570
  • 财政年份:
    2020
  • 资助金额:
    $ 52.21万
  • 项目类别:
Role of mTORC1 in Retinal Ganglion Cell Physiology and Disease
mTORC1 在视网膜神经节细胞生理和疾病中的作用
  • 批准号:
    10229613
  • 财政年份:
    2020
  • 资助金额:
    $ 52.21万
  • 项目类别:
Inflammatory Resolution and Vascular Restoration in Diabetic Retinopathy
糖尿病视网膜病变的炎症消退和血管恢复
  • 批准号:
    10222701
  • 财政年份:
    2018
  • 资助金额:
    $ 52.21万
  • 项目类别:
Inflammatory Resolution and Vascular Restoration in Diabetic Retinopathy
糖尿病视网膜病变的炎症消退和血管恢复
  • 批准号:
    9761528
  • 财政年份:
    2018
  • 资助金额:
    $ 52.21万
  • 项目类别:
Inflammatory Resolution and Vascular Restoration in Diabetic Retinopathy
糖尿病视网膜病变的炎症消退和血管恢复
  • 批准号:
    10459620
  • 财政年份:
    2018
  • 资助金额:
    $ 52.21万
  • 项目类别:
Inflammatory Resolution and Vascular Restoration in Diabetic Retinopathy
糖尿病视网膜病变的炎症消退和血管恢复
  • 批准号:
    9979905
  • 财政年份:
    2018
  • 资助金额:
    $ 52.21万
  • 项目类别:
Bone Marrow Neuropathy Drives Diabetic Retinopathy
骨髓神经病变导致糖尿病视网膜病变
  • 批准号:
    8735950
  • 财政年份:
    2013
  • 资助金额:
    $ 52.21万
  • 项目类别:
Bone Marrow Neuropathy Drives Diabetic Retinopathy
骨髓神经病变导致糖尿病视网膜病变
  • 批准号:
    8731390
  • 财政年份:
    2013
  • 资助金额:
    $ 52.21万
  • 项目类别:
Regulation of Retinal Cell Death in Diabetes
糖尿病视网膜细胞死亡的调节
  • 批准号:
    9124905
  • 财政年份:
    2010
  • 资助金额:
    $ 52.21万
  • 项目类别:
Regulation of Retinal Cell Death in Diabetes
糖尿病视网膜细胞死亡的调节
  • 批准号:
    8174942
  • 财政年份:
    2010
  • 资助金额:
    $ 52.21万
  • 项目类别:

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