Dopamine Homeostasis, Vesicles & Neurodegeneration

多巴胺稳态,囊泡

基本信息

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

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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

Angiotensin and Neurodegeneration
血管紧张素和神经变性
  • 批准号:
    7586312
  • 财政年份:
    2008
  • 资助金额:
    $ 30.72万
  • 项目类别:
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:
    $ 30.72万
  • 项目类别:
Adenosine, Glutamate and Neurodegeneration
腺苷、谷氨酸和神经变性
  • 批准号:
    7071273
  • 财政年份:
    2005
  • 资助金额:
    $ 30.72万
  • 项目类别:
Adenosine, Glutamate and Neurodegeneration
腺苷、谷氨酸和神经变性
  • 批准号:
    7418642
  • 财政年份:
    2005
  • 资助金额:
    $ 30.72万
  • 项目类别:
Adenosine, Glutamate and Neurodegeneration
腺苷、谷氨酸和神经变性
  • 批准号:
    6963568
  • 财政年份:
    2005
  • 资助金额:
    $ 30.72万
  • 项目类别:
Adenosine, Glutamate and Neurodegeneration
腺苷、谷氨酸和神经变性
  • 批准号:
    7167839
  • 财政年份:
    2005
  • 资助金额:
    $ 30.72万
  • 项目类别:
Adenosine, Glutamate and Neurodegeneration
腺苷、谷氨酸和神经变性
  • 批准号:
    7248636
  • 财政年份:
    2005
  • 资助金额:
    $ 30.72万
  • 项目类别:
Dopamine Homeostasis, Vesicles & Neurodegeneration
多巴胺稳态,囊泡
  • 批准号:
    6320413
  • 财政年份:
    2001
  • 资助金额:
    $ 30.72万
  • 项目类别:
Dopamine Homeostasis, Vesicles & Neurodegeneration
多巴胺稳态,囊泡
  • 批准号:
    6540439
  • 财政年份:
    2001
  • 资助金额:
    $ 30.72万
  • 项目类别:
Dopamine Homeostasis, Vesicles & Neurodegeneration
多巴胺稳态,囊泡
  • 批准号:
    6639763
  • 财政年份:
    2001
  • 资助金额:
    $ 30.72万
  • 项目类别:

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