GENETIC AND BIOCHEMICAL EVENTS IN AB-INDUCED APOPTOSIS
GENETIC AND BIOCHEMICAL EVENTS IN AB-INDUCED APOPTOSIS
批准号:
2001588
负责人:
Carl Wayne Cotman
金额:
$15.72万
依托单位国家:
美国
项目类别:
财政年份:
1995
资助国家:
美国
项目状态:
已结题
起止时间:
1995-01-15 至 1997-12-31
中文摘要
描述:小肽β-淀粉样蛋白,AB,已被牵连,
阿尔茨海默病的神经退化过程 申请人已经
在定义AB毒性方面发挥了重要作用,现在已经获得了数据
表明它通过凋亡途径导致培养的神经元死亡
表现出膜泄漏,染色质浓缩和DNA
碎片化经典的凋亡或程序性细胞死亡被定义为
形态学上通过最初的表面blabbing,染色质凝聚和
核收缩,随后核碎裂成核体
和多核糖体分散,而有限的ER仍然和线粒体
保持正常。 只有在继发性坏死的晚期,
质膜解体。 相反,坏死性细胞死亡是
以ER、线粒体和膜的早期扩张为特征
破坏 该建议是定义细胞的序列,
由对AB的反应引发的分子事件,
诱导立即早期基因,IEGs,(c-fos和c-jun以及随后的c-fos和c-jun),
myc和junB)以及钙和其他第二信使在
诱导fos和jun和DNA断裂。 申请人已经
初步数据表明,AB诱导IEG,c-fos和c-jun。
细胞系统中,反义抑制fos和jun可抑制
凋亡 目标1提出定义c-jun的详细时间过程
和c-fos诱导。 目标2建议使用反义
寡核苷酸阻断这种诱导,并确定细胞死亡是否是
防止。 在其他系统中,细胞凋亡已被证明会导致
fos和jun诱导,时间过程与DNA的时间过程平行
碎片化 目的4是确定DNA的时间过程
碎片化,看看c-fos和c-jun的时间过程是否相同
诱导 还建议确定反义是否
如目的2中的处理防止DNA片段化。 C-myc是
另一种IEG通过反义和反义寡核苷酸参与细胞凋亡,
表达的研究,还有一些其他的,包括bcl-2,bcl-2,
x、ced-3和ced-9。 目标3旨在确定其他方面的变化
IEGs,重点关注对AB的c-myc和junB反应。 根据工作,
其他凋亡系统和其他研究AB毒性的实验室
作为他们自己的数据,申请人假设AB细胞凋亡是
介导的细胞内钙离子的瞬时上升,随后是
在DNA断裂之前的延迟上升。 在目标5中,申请人
旨在更好地定义钙作为AB介导剂的作用,
使用钙成像的反应,DNA的组织化学评估
使用游离3 '-OH基团的原位末端标记的片段化,
碎片和光学显微镜。
英文摘要
DESCRIPTION: The small peptide beta-amyloid, AB, has been implicated in
the neurodegenerative process in Alzheimer's disease. The applicant has
played a major role in defining AB toxicity and has now obtained data
showing that it causes cultured neurons to die by an apoptotic pathway
exhibiting membrane blabbing, chromatin condensation and DNA
fragmentation. Classically apoptotic or programmed cell death was defined
morphologically by initial surface blabbing, chromatin condensation and
nuclear shrinkage, followed by nuclear fragmentation into nuclear bodies
and polyribosome dispersal while limited ER remains and mitochondria
remain normal. Only late in the secondary necrosis stage does the
plasma membrane disintegrate. In contrast, necrotic cell death is
characterized by early dilation of the ER and mitochondria and membrane
disruption. The proposal is to define the sequence of cellular and
molecular events initiated by the response to AB focussing on the
induction of immediate early genes, IEGs, (c-fos and c-jun and later c-
myc and junB) and the role of calcium and other second messengers in
inducing fos and jun and DNA fragmentation. The applicant has
preliminary data that AB induces the IEGs, c-fos and c-jun. In other
cell systems, antisense inhibition of fos and jun has inhibited
apoptosis. Aim 1 proposes to define the detailed time course of c-jun
and c-fos induction in response to AB. Aim 2 proposes to use antisense
oligos to block this induction and determine whether cell death is
prevented. In other systems where apoptosis has been shown to result in
fos and jun induction, the time course parallels that of DNA
fragmentation. Aim 4 is to determine the time course for DNA
fragmentation and see if the time course is the same for c-fos and c-jun
induction. It is also proposed to determine whether anti-sense
treatment as in aim 2 protects against DNA fragmentation. C-myc is
another IEG shown to be involved in apoptosis by antisense and
expression studies and there are a number of others including bcl-2, bcl-
x, ced-3 and ced-9. Aim 3 is directed at determining changes in other
IEGs, focussing on c-myc and junB in response to AB. Based on work in
other apoptotic systems and other labs working on AB toxicity as well
as their own data, the applicants hypothesize that AB apoptosis is
mediated by a transient rise in intracellular calcium, followed by a
delayed rise which precedes DNA fragmentation. In aim 5, the applicant
seeks to better define the role of calcium as a mediator of the AB
response using calcium imaging, histochemical assessment of DNA
fragmentation using in situ end labelling of free 3'-OH groups on
fragments and light microscopy.
期刊论文(4)
专著(0)
科研奖励(0)
会议论文
Attenuation of beta-amyloid neurotoxicity in vitro by potassium-induced depolarization.
通过钾诱导的去极化在体外减弱β-淀粉样蛋白神经毒性。
DOI:
10.1046/j.1471-4159.1996.67041774.x
发表时间:
1996
期刊:
Journal of neurochemistry
影响因子:
4.7
作者:
[Pike,CJ, Balázs,R, Cotman,CW]
通讯作者:
Cotman,CW
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A Novel Approach to Study Synaptic Plasticity in Isolated Synaptosomes using Flow Cytometry
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批准号:7951064
-
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-
批准号:6932808
-
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Brain Aging & Gene Expression Patterns Using Microarrays
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批准号:6723376
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依托单位:
AO (AntiOxidant) Protocol
-
批准号:7045538
-
项目类别:
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资助金额:$1.89万
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Brain Aging & Gene Expression Patterns Using Microarrays
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批准号:6806563
-
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依托单位:
海外基金