Role of Human-Specific Cathepsin V Protease in the Production of Opioid and Related Peptide Neurotransmitters

人类特异性组织蛋白酶 V 蛋白酶在阿片类药物和相关肽神经递质生产中的作用

基本信息

  • 批准号:
    9215425
  • 负责人:
  • 金额:
    $ 15.6万
  • 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:
    2015-09-30 至 2019-07-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): This project addresses the fundamental question of "What `human' protease mechanisms are responsible for producing active peptide neurotransmitters, neuropeptides, that are a fundamental requirement for all brain and nervous system functions?" The unique hypothesis to address this question is that human-specific cathepsin V, combined with proteases identified in non-human animal models for neuropeptide production, participates in producing active neuropeptides. Fundamental knowledge of the human protease mechanisms for producing neuropeptides are relevant to neuropeptide regulation in neurological and mental health throughout aging, and which are impacted by environmental conditions including drugs of abuse. Studies in mice have demonstrated the important role of mouse cathepsin L in secretory vesicles for producing opioid and other neuropeptides. Interestingly, human-specific cathepsin V is the closest human homologue to mouse cathepsin L, suggesting a role for cathepsin V in neuropeptide production. The human-specific cathepsin V gene is not present in mouse or other species. We investigated human cathepsin V and found that it participates as a significant protease for enkephalin neuropeptide production. These findings lead to the goal of this `human focused' project to define the human protease mechanisms for neuropeptide production by cathepsin V, combined with cathepsin L and the PC1/3 & PC2 convertases that function in non-human species for neuropeptide production. Human induced pluripotent stem cell (hiPSC) neurons produce numerous neuropeptides and will be used as an innovative model for human protease mechanisms in neuropeptide biosynthesis. Parallel studies of neuropeptides and processing proteases in human brain regions rich in neuropeptides will support findings gained from the hiPSC model. Innovative neuropeptidomics mass spectrometry will identify neuropeptide profiles in an unbiased and high throughput manner. The first aim will define the cellular role in hiPSC neurons of cathepsin V in the production of opioid neuropeptides with comparison to cathepsin L, PC1/3, and PC2 proteases by gene silencing and expression, combined with mass spectrometry peptide identifications. The second aim will conduct in vitro biochemical studies of cathepsin V processing of opioid pro-neuropeptides compared to cathepsin L, PC1/3, and PC2, to define cleavage sites, peptide products, and kinetic efficiencies, with parallel analyses in human brain regions. The third aim will investigate diverse neuropeptides by neuropeptidomics of hiPSC neurons and human brain tissues to evaluate the role of these human proteases in producing diverse neuropeptides. Results will define the basic human protease mechanisms for peptide neurotransmitter production that is fundamental for brain and nervous system functions in health and disease.


项目成果

期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Vivian Y. H Hook其他文献

Vivian Y. H Hook的其他文献

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{{ truncateString('Vivian Y. H Hook', 18)}}的其他基金

Development of Molecular Probe Inhibitors of Pathogenic, Cytosolic Cathespin B in Traumatic Brain Injury and Alzheimers Disease Neurodegeneration
外伤性脑损伤和阿尔茨海默病神经变性中致病性胞质组织蛋白酶 B 的分子探针抑制剂的开发
  • 批准号:
    10451837
  • 财政年份:
    2019
  • 资助金额:
    $ 15.6万
  • 项目类别:
Development of molecular probe inhibitors of pathogenic, cytosolic cathespin B in traumatic brain injury and Alzheimers Disease neurodegeneration
开发创伤性脑损伤和阿尔茨海默病神经变性中致病性胞质组织蛋白酶 B 的分子探针抑制剂
  • 批准号:
    10199079
  • 财政年份:
    2019
  • 资助金额:
    $ 15.6万
  • 项目类别:
Development of Molecular Probe Inhibitors of Pathogenic, Cytosolic Cathespin B in Traumatic Brain Injury and Alzheimers Disease Neurodegeneration
外伤性脑损伤和阿尔茨海默病神经变性中致病性胞质组织蛋白酶 B 的分子探针抑制剂的开发
  • 批准号:
    10652388
  • 财政年份:
    2019
  • 资助金额:
    $ 15.6万
  • 项目类别:
Role of Human-Specific Cathepsin V Protease in the Production of Opioid and Related Peptide Neurotransmitters
人类特异性组织蛋白酶 V 蛋白酶在阿片类药物和相关肽神经递质生产中的作用
  • 批准号:
    9007800
  • 财政年份:
    2015
  • 资助金额:
    $ 15.6万
  • 项目类别:
Aminopeptidases for Neurotoxic Pyroglutamate Beta-Amyloid of Alzheimers Disease
氨基肽酶治疗阿尔茨海默病的神经毒性焦谷氨酸β-淀粉样蛋白
  • 批准号:
    8583849
  • 财政年份:
    2013
  • 资助金额:
    $ 15.6万
  • 项目类别:
Aminopeptidases for Neurotoxic Pyroglutamate Beta-Amyloid of Alzheimers Disease
氨基肽酶治疗阿尔茨海默病的神经毒性焦谷氨酸β-淀粉样蛋白
  • 批准号:
    8690732
  • 财政年份:
    2013
  • 资助金额:
    $ 15.6万
  • 项目类别:
Proteolytic Fragments of Mutant Huntingtin Protein in HD Brain Regions
HD 脑区突变亨廷顿蛋白的蛋白水解片段
  • 批准号:
    8073938
  • 财政年份:
    2010
  • 资助金额:
    $ 15.6万
  • 项目类别:
Proteolytic Fragments of Mutant Huntingtin Protein in HD Brain Regions
HD 脑区突变亨廷顿蛋白的蛋白水解片段
  • 批准号:
    7991243
  • 财政年份:
    2010
  • 资助金额:
    $ 15.6万
  • 项目类别:
Prohormone processing: NPY and Catestatin Peptide Production
激素原加工:NPY 和儿联蛋白肽生产
  • 批准号:
    7844954
  • 财政年份:
    2009
  • 资助金额:
    $ 15.6万
  • 项目类别:
Sympathochromaffin cell culture
交感嗜铬细胞培养
  • 批准号:
    7844961
  • 财政年份:
    2009
  • 资助金额:
    $ 15.6万
  • 项目类别:

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