Synaptic Proteins, Trophic Factors and Neurodegeneration
Synaptic Proteins, Trophic Factors and Neurodegeneration
批准号:
6796986
负责人:
Gloria E. Meredith
金额:
$7.8万
依托单位国家:
美国
项目类别:
财政年份:
2001
资助国家:
美国
项目状态:
已结题
起止时间:
2001-05-01 至 2005-04-30
关键词:
Lewy body Parkinson's disease alpha synuclein brain derived neurotrophic factor cell death electron microscopy fluorescence microscopy image processing immunocytochemistry in situ hybridization laboratory mouse methylphenyltetrahydropyridine neural degeneration neurochemistry neurons polymerase chain reaction protein structure function statistics /biometry substantia nigra synapses
中文摘要
描述(由申请人提供):最基本的问题之一
与人类疾病中神经退行性变的进行性本质有关的是,
神经元死亡。保护神经细胞免于形态衰退和死亡
需要阻断抑制神经修复的内在因素本
建议,我们提供了一个创新的方法来研究这些因素,
在一种新的小鼠模型中,
丧失和不可逆的黑质纹状体变性。我们建议跟踪变化
一种关键的突触蛋白,a-突触核蛋白,在其天然环境中,
突触前末梢和神经毒性条件下,当它成为
不溶并积累。我们将进一步将这些变化与
神经营养支持我们已经建立了一个动物方案,通过治疗C57/BL
小鼠用丙磺舒250 mg/kg和MPTP 250 mg/kg的10个剂量的组合方案,
25 mg/kg,连续5周。这些小鼠表现出黑质纹状体的缓慢、进行性损失,
多巴胺能功能至少6个月,模仿PD,没有迹象表明
复苏药物治疗后三周,
黑质(SN)细胞的数量和
突触下分布和α-突触核蛋白免疫反应终末密度。
这些变化可能预示着一系列事件的开始,
细胞死亡在本提案中,我们将重点关注
多巴胺能神经元在SN和他们的输入,并提出了三个具体的
它的目的是通过一系列的假设来解决。具体来说,我们计划
1)确定SN中突触的起源和神经化学表型,
含有α-突触核蛋白,并确定MPTP +丙磺舒治疗是否导致
2)在MPTP+P模型中,确定时间
细胞死亡和突触核蛋白阳性突触之间的关系,
多巴胺功能和行为; 3)确定是否a-突触核蛋白的变化
表达和产生通过改变的神经营养支持而沉淀。的
我们研究的总体目标是了解
突触蛋白,a-突触核蛋白,神经营养支持,特别是脑源性
神经营养因子(BDNF)及其各自在PD形式的
神经变性这项研究的结果应该有助于阐明目标
可以实施神经保护策略的领域。
英文摘要
Description (Provided by applicant): One of the most fundamental questions
related to the progressive nature of neurodegeneration in human disease is how
neurons die. Protecting nerve cells against morphological decline and death
requires blocking intrinsic factors that inhibit neural repair. In the present
proposal, we offer an innovative approach to study those factors that are
active in Parkinson's disease (PD) in a new mouse model that shows synaptic
loss and irreversible nigrostriatal degeneration. We propose to track changes
of a key synaptic protein, a-synuclein, both in its native environment at
presynaptic terminals and under neurotoxic conditions, when it becomes
insoluble and accumulates. We will further correlate those changes with altered
neurotrophic support. We have established an animal protocol by treating C57/bl
mice with a combined regimen of 10 doses of probenecid at 250mg/kg and MPTP at
25mg/kg for 5 weeks. These mice show a slow, progressive loss of nigrostriatal
dopaminergic function for at least 6 months, that mimics PD, with no signs of
recovery. Three weeks after drug treatment, there is a significant reduction in
the number of substantia nigra (SN) cells and dramatic changes in the
subsynaptic distribution and density of a-synuclein-immunoreactive terminals.
These changes could signal the beginning of a chain of events that leads to
cell death. In this proposal, we will focus on the progressive deterioration of
dopaminergic neurons in the SN and their inputs, and present three specific
aims to be addressed through a series of hypotheses. Specifically, we plan to
1) ascertain the origin and neurochemical phenotype of synapses in the SN that
contain a-synuclein and to establish whether MPTP + probenecid treatment leads
to their degeneration; 2) determine, in the MPTP+P model, the temporal
relationships between cell death and a-synuclein-positive synapses, decline in
dopamine function and behavior; and 3) ascertain whether changes in a-synuclein
expression and production are precipitated by altered neurotrophic support. The
overall objective of our research is to understand the relationship between the
synaptic protein, a-synuclein, neurotrophic support, especially brain-derived
neurotrophic factor (BDNF) and their respective roles in the PD form of
neurodegeneration. The findings of this research should shed light on target
areas where neuroprotection strategies can be implemented.
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会议论文
Mechanisms underlying reward-related synaptogenesis
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批准号:6671277
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项目类别:
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资助金额:$27.05万
-
财政年份:2003
-
负责人:Gloria E. Meredith
-
依托单位:
Mechanisms underlying reward-related synaptogenesis
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批准号:6785457
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项目类别:
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资助金额:$25.63万
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财政年份:2003
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负责人:Gloria E. Meredith
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依托单位:
Mechanisms underlying reward-related synaptogenesis
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批准号:6888155
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项目类别:
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资助金额:$25.62万
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财政年份:2003
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负责人:Gloria E. Meredith
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依托单位:
Mechanisms underlying reward-related synaptogenesis
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批准号:7074580
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项目类别:
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资助金额:$25.01万
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财政年份:2003
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负责人:Gloria E. Meredith
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依托单位:
Mechanisms underlying reward-related synaptogenesis
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批准号:7227223
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项目类别:
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资助金额:$24.29万
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财政年份:2003
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负责人:Gloria E. Meredith
-
依托单位:
Mechanisms underlying reward-related synaptogenesis
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批准号:7894849
-
项目类别:
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资助金额:$30.8万
-
财政年份:2003
-
负责人:Gloria E. Meredith
-
依托单位:
Mechanisms underlying reward-related synaptogenesis
-
批准号:7741980
-
项目类别:
-
资助金额:$30.8万
-
财政年份:2003
-
负责人:Gloria E. Meredith
-
依托单位:
Synaptic Proteins, Trophic Factors and Neurodegeneration
-
批准号:6639800
-
项目类别:
-
资助金额:$27.6万
-
财政年份:2001
-
负责人:Gloria E. Meredith
-
依托单位:
Synaptic Proteins, Trophic Factors and Neurodegeneration
-
批准号:6664894
-
项目类别:
-
资助金额:$2.5万
-
财政年份:2001
-
负责人:Gloria E. Meredith
-
依托单位:
Synaptic Proteins, Trophic Factors and Neurodegeneration
-
批准号:6665235
-
项目类别:
-
资助金额:$28.68万
-
财政年份:2001
-
负责人:Gloria E. Meredith
-
依托单位:
Synaptic Proteins, Trophic Factors and Neurodegeneration
-
批准号:6344380
-
项目类别:
-
资助金额:$29.0万
-
财政年份:2001
-
负责人:Gloria E. Meredith
-
依托单位:
Synaptic Proteins, Trophic Factors and Neurodegeneration
-
批准号:6540486
-
项目类别:
-
资助金额:$1.4万
-
财政年份:2001
-
负责人:Gloria E. Meredith
-
依托单位:
Synaptic Proteins, Trophic Factors and Neurodegeneration
-
批准号:6740206
-
项目类别:
-
资助金额:$28.68万
-
财政年份:2001
-
负责人:Gloria E. Meredith
-
依托单位:
MECHANISMS OF EFFERENT ACTIVATION IN THE AUDITORY SYSTEM
-
批准号:3053576
-
项目类别:
-
资助金额:$0.03万
-
财政年份:1986
-
负责人:Gloria E. Meredith
-
依托单位:
MECHANISMS OF EFFERENT ACTIVATION IN THE AUDITORY SYSTEM
-
批准号:3053575
-
项目类别:
-
资助金额:$0.3万
-
财政年份:1986
-
负责人:Gloria E. Meredith
-
依托单位:
MECHANISMS OF EFFERENT ACTIVATION IN THE AUDITORY SYSTEM
-
批准号:3053574
-
项目类别:
-
资助金额:$2.2万
-
财政年份:1986
-
负责人:Gloria E. Meredith
-
依托单位:
MECHANISMS OF CENTRAL AUDITORY PROCESSING
-
批准号:3053577
-
项目类别:
-
资助金额:$1.7万
-
财政年份:1984
-
负责人:Gloria E. Meredith
-
依托单位:
MECHANISMS OF CENTRAL AUDITORY PROCESSING
-
批准号:3053578
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项目类别:
-
资助金额:$0.3万
-
财政年份:1984
-
负责人:Gloria E. Meredith
-
依托单位:
海外基金