Dopamine Homeostasis, Vesicles & Neurodegeneration
多巴胺稳态,囊泡
基本信息
- 批准号:6639763
- 负责人:
- 金额:$ 30.35万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2001
- 资助国家:美国
- 起止时间:2001-04-01 至 2005-03-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
DESCRIPTION: (Verbatim from the Applicant's Abstract) Parkinson's disease is a
debilitating motor impairment disorder due to loss of nigral dopamine neurons.
Mitochondrial defects in PD patients implicate energy impairment and metabolic
stress as potential factors in its etiology. Moreover, DA oxidation products
may add to the oxidative burden within DA neurons which, coupled with a
persistent metabolic stress, may lead to neurodegeneration. Epidemiological
studies link PD with environmental exposure to substances such as pesticides. -
Many pesticides are mitochondrial inhibitors. A potential form of protection
against mitochondrial toxins (i.e., MPP+) may be their sequestration into
synaptic vesicles of DA neurons. The goal of this project is to gain an
understanding of the role of vesicles, the vesicular monoamine transporter
(VMAT2) and DA in modulating neurodegeneration produced by mitochondrial
toxins. One hypothesis is that the actions of mitochondrial toxins can be
modulated in contrasting ways depending on whether the toxins are sequestered
into vesicles. If sequestered, toxin exposure could be abrogated. In contrast,
disruption of vesicular function toxin could lead to disturbed DA homeostasis
and enhanced toxicity since it would remove the toxin from interaction with
mitochondria. In Aim 1 several mitochondrial toxins will be examined for their
ability to interfere with vesicle function (i.e. to inhibit DA uptake into
isolated rat membrane vesicles). In aim 2, rat mesencephalic cultures or rat
striata will be exposed to mitochondrial toxins following VMAT2 inhibition to
determine if toxicity is modified. To examine the hypothesis that disturbed DA
homeostasis contributes to degeneration produced by metabolic stress, two
approaches will be used. First, DA will be depleted prior to exposure of
culture or rat striata to a mitochondrial inhibitor. Second, vesicle contents
(DA) will be released into the cytosol after exposure to the mitochondrial
toxin to examine if augmented disruption of DA homeostasis during the metabolic
stress enhances toxicity. Additionally, the hypothesis that substances that are
not themselves mitochondrial inhibitors, but can disrupt DA storage in vesicles
may amplify damage during episodes of metabolic stress will be examined in Aim
3. In aim 4 the hypothesis that early events such as oxidative stress leads to
loss of vesicle function, disruption of DA homeostasis and exacerbation of
neurodegeneration produced by toxins will be investigated. Isolated vesicles
will be tested for their sensitivity to oxidizing and reducing conditions.
Results from these studies will provide novel and relevant information as to
the contribution of VMAT2 containing vesicles in neuroprotection as well as in
neurodegeneration of DA neurons during metabolic stress.
描述:(摘自申请人摘要)帕金森病是一种疾病
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Patricia K Sonsalla其他文献
Patricia K Sonsalla的其他文献
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{{ truncateString('Patricia K Sonsalla', 18)}}的其他基金
Developing and Improving Institutional Animal Resources
开发和改善机构动物资源
- 批准号:
6909640 - 财政年份:2005
- 资助金额:
$ 30.35万 - 项目类别:
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