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(由申请人提供):亨廷顿氏病(HD)是一种遗传性神经退行性疾病,其特征在于运动和认知障碍。基于在人类HD脑和表达突变htt的转基因小鼠中的研究,具有扩展的多聚谷氨酰胺重复的突变亨廷顿蛋白(htt)是HD的原因。htt的蛋白水解片段参与HD疾病过程。在人脑中,已经证实了HD脑中的N-末端htt片段。在转基因小鼠中表达突变的N-末端htt片段诱导类似HD的行为特征和神经元缺陷。值得注意的是,已经证明了人类HD脑中htt N-和C-末端片段的不同模式。然而,这些在体内脑htt蛋白水解片段的鉴定尚未确定。关键的,未解决的问题是什么是主要序列的htt蛋白水解片段在受影响的纹状体和皮质的人类HD大脑?因此,本提案的目标是评价来自人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片段的一级序列。 第一个目的是评价来自表达全长htt的转基因HD小鼠模型的小鼠脑区域的体内htt片段的肽序列。Htt片段将通过提供高度富集的htt蛋白用于纯化的蛋白色谱树脂进行纯化;纯化将包括具有充分表征的抗血清的抗htt亲和柱,所述抗血清识别全长htt的N-末端区域、N-结构域和C-结构域区域。纯化的htt片段将通过质谱法进行肽测序,包括N-和C-末端区域的测序。结果将表明表达全长htt的HD小鼠模型中htt蛋白水解片段的肽序列。第二个目的是通过质谱法评估从人HD脑区域-皮质和纹状体-纯化的人htt片段的肽序列。从人脑区域纯化htt片段将利用aim 1中为小鼠htt片段开发的纯化程序。纯化的人htt片段的质谱分析将如从小鼠脑分离的htt片段所述进行。结果将提供人类HD脑中htt片段序列的关键知识。 该项目的结果是必不可少的HD研究的下一阶段,以确定最神经毒性的htt片段,阐明产生毒性htt片段的蛋白酶的全谱,并向前迈进,以药物发现的蛋白酶抑制剂,可能会减少生产的htt片段。该项目将对未来开发HD的有效治疗方法具有非常高的益处。 公共卫生关系:该项目的目标是评估已知与亨廷顿病(HD)发展有关的体内突变亨廷顿(htt)蛋白片段的一级肽序列。HD患者脑中的这些htt片段尚未完全确定其一级氨基酸序列,这将在本项目中通过纯化和当前质谱法对其进行分析来实现。从该项目中获得的知识对于理解HD的关键htt机制至关重要,这将提供改善疾病状况的未来策略。

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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