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

基本信息

  • 批准号:
    7991243
  • 负责人:
  • 金额:
    $ 23.18万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-06-01 至 2012-05-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Huntington's Disease (HD) is an inherited neurodegenerative disorder characterized by motor and cognitive impairments. The mutant huntingtin (htt) protein with expanded polyglutamine repeats are responsible for HD based on studies in human HD brains and in transgenic mice expressing mutant htt. Proteolytic fragments of htt are involved in the HD disease process. In human brain, N-terminal htt fragments in HD brains have been demonstrated. Expression of mutant N-terminal htt fragments in transgenic mice induces behavioral features and neuronal deficits that resemble HD. Notably, distinct patterns of htt N- and C-terminal fragments in human HD brains has been demonstrated. However, identification of these in vivo brain htt proteolytic fragments has not yet been determined. The critical, unsolved question is what are the primary sequences of htt proteolytic fragments in affected striatum and cortex of human HD brains? Therefore, the goal of this proposal will be to evaluate the primary sequences of N-terminal, N-domain, and C-domain htt fragments from human HD striatum and cortex, as well as from HD mouse models that express full-length htt. The first aim will evaluate the peptide sequences of in vivo htt fragments from mouse brain regions of transgenic HD mouse models that express full-length htt. Htt fragments will be purified by protein chromatographic resins that provide highly enriched htt proteins for purification; purification will include anti- htt affinity columns with well-characterized antisera that recognize the N-terminal region, N-domain, and C- domain areas of full-length htt. Purified htt fragments will be subjected to peptide sequencing by mass spectrometry, including sequencing of N- and C-terminal regions. Results will indicate peptide sequences of htt proteolytic fragments in mouse models of HD that express full-length htt. The second aim will evaluate the peptide sequences of human htt fragments purified from human HD brain regions - cortex and striatum - by mass spectrometry. The purification of htt fragments from human brain regions will utilize the purification procedure developed in aim 1 for mouse htt fragments. Mass spectrometry of purified human htt fragments will be conducted as described for htt fragments isolated from mouse brain. Results will provide key knowledge of the htt fragment sequences in human HD brain. Results of this project are essential for the next stages of HD research to define the most neurotoxic htt fragments, to elucidate the full spectrum of proteases that generate toxic htt fragments, and to move forward to drug discovery of protease inhibitors that may reduce production of htt fragments. This project will have extraordinarily high benefit for future development of effective therapeutic treatments for HD. PUBLIC HEALTH RELEVANCE: The goal of this project is to evaluate the primary peptide sequences of the in vivo mutant huntingtin (htt) protein fragments that are known to be responsible for the development of Huntington's disease (HD). These htt fragments in HD brains of patients have not yet been completely defined with respect to their primary amino acid sequences, which will be achieved in this project by their analyses by purification and current mass spectrometry approaches. The knowledge gained from this project is essential for understanding key htt mechanisms underlying HD, which will provide future strategies to improve the disease condition.
描述(申请人提供):亨廷顿病(HD)是一种遗传性神经退行性疾病,以运动和认知障碍为特征。基于对人类HD大脑和表达突变的HTT的转基因小鼠的研究,带有扩展的多谷氨酰胺重复序列的突变的Huntingtin(HTT)蛋白与HD有关。HTT的蛋白水解性片段参与了HD的发病过程。在人脑中,已证实HD脑中存在N-末端HTT片段。在转基因小鼠中表达突变的N端HTT片段会导致类似HD的行为特征和神经元缺陷。值得注意的是,人类HD大脑中HTT的N-末端和C-末端片段的不同模式已经被证明。然而,对这些活体脑HTT蛋白水解物片段的鉴定还没有确定。关键的、悬而未决的问题是,人类HD大脑中受影响的纹状体和皮质中HTT蛋白分解片段的主要序列是什么?因此,这项建议的目标将是评估人类HD纹状体和皮质以及表达全长HTT的HD小鼠模型的N-末端、N-结构域和C-结构域HTT片段的初级序列。第一个目标是评估体内表达全长hTT的转基因HD小鼠模型小鼠脑区域中hTT片段的多肽序列。HTT片段将通过提供高度浓缩的HTT蛋白的蛋白层析树脂进行纯化;纯化将包括抗HTT亲和柱和特征良好的抗血清,这些抗血清识别全长HTT的N-末端区域、N-结构域和C-结构域区。纯化的HTT片段将通过质谱仪进行多肽测序,包括N-末端和C-末端区域的测序。结果将显示在HD小鼠模型中表达全长HTT的HTT蛋白分解片段的肽序列。第二个目标将通过质谱学方法评估从人类HD脑区--皮质和纹状体--提纯的人HTT片段的肽序列。从人脑区域提纯hTT片段将利用目标1中为小鼠hTT片段开发的提纯程序。对纯化的人HTT片段进行质谱分析,如从小鼠脑中分离的HTT片段所述。这些结果将提供人类HD脑中HTT片段序列的关键知识。该项目的结果对于下一阶段的HD研究至关重要,以确定神经毒性最强的HTT片段,阐明产生有毒HTT片段的蛋白水解酶的全谱,并推进可能减少HTT片段产生的蛋白酶抑制剂的药物发现。该项目将对未来HD有效治疗方法的开发具有非常高的效益。 公共卫生相关性:该项目的目标是评估体内突变的Huntingtin(HTT)蛋白片段的初级肽序列,这些片段是已知导致亨廷顿病(HD)发生的原因。HD患者大脑中的这些HTT片段尚未完全确定其主要氨基酸序列,这将在本项目中通过纯化和当前的质谱学方法进行分析来实现。从这个项目中获得的知识对于理解HD背后的关键HTT机制至关重要,这将为未来改善疾病状况提供策略。

项目成果

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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:
    $ 23.18万
  • 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:
    $ 23.18万
  • 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:
    $ 23.18万
  • 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:
    9215425
  • 财政年份:
    2015
  • 资助金额:
    $ 23.18万
  • 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:
    $ 23.18万
  • 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:
    $ 23.18万
  • 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:
    $ 23.18万
  • 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:
    $ 23.18万
  • 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:
    $ 23.18万
  • 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:
    $ 23.18万
  • 项目类别:

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