ALTERATION OF CALCIUM CHANNEL FUNCTION IN BRAIN AGING
大脑老化过程中钙通道功能的改变
基本信息
- 批准号:6267223
- 负责人:
- 金额:$ 14.19万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1998
- 资助国家:美国
- 起止时间:1998-05-01 至 1999-03-31
- 项目状态:已结题
- 来源:
- 关键词:NMDA receptors acetylcholine adenosine aging biophysics calcium channel calcium flux calmodulin dependent protein kinase enzyme activity enzyme inhibitors gamma aminobutyrate glutamates hippocampus laboratory rat neuropharmacology neurotrophic factors polymerase chain reaction protein kinase A protein kinase C pyramidal cells voltage /patch clamp voltage gated channel
项目摘要
cA2+ influx through voltage-gated Ca2+ channels is essential for
neurotransmitter release, synaptic plasticity, electrical waveform
processing and modification of gene expression in neurons. Yet Ca2+ can
also have harmful effects in neurons; modest, sustained elevation of
cytoplasmic Ca2+ concentration leads to neuronal degeneration, and
ultimately, cell death. Accumulation of such Ca2+ insults has been
hypothesized to underlie at least some aspects of brain aging and dementia.
As dominant contributors to neuronal Ca2+ signalling, Ca2+ channels
represent major potential targets in the search for sources of aging-
related neuronal malfunction. Indeed, it has been established over the
last several years that the contribution of voltage-gated Ca2+ channels to
electrical activity in neurons changes with aging. The principal goal of
Project 2 is to delineate mechanisms of aging-induced alteration in the
activity of voltage-gated Ca2+ channels in brain neurons. The research
plan is directed towards three specific aims:
(1) What biophysical properties of Ca2+ channels change with aging?
(2) Does aging dependent alteration of Ca2+ channel activity arise from
changes intrinsic to the Ca2+ channel?
(3) Does aging-dependent alteration of Ca2+ channel activity result from
extrinsic influences?
The experimental approach takes of advantage of the ability of patch-clamp
electrophysiological techniques to detect critical, but potentially
subtile, changes in Ca2+ channel behavior in aging. Properties that may
change include (i) amplitude of Ca2+ current, (ii) the voltage-dependencies
of channel activation, inactivation and deactivation, (iii) efficiency of
channel opening, (iv) Ca2+ permeability through the channel or (v)
sensitivity to modulation by neurotransmitter-receptors. All of these
parameters will be measured and compared as a function of neuron age. The
biophysical and pharmacological work will be complemented by efforts to
determine whether channel subunit makeup changes with aging. Tissue and
single-cell mRNA analyses will be used as a first step towards this goal.
The combined electrophysiological and molecular biological approach will
provide a synergistic effort to track down the origins of Ca2+ channel
dysfunction related to brain aging. Understanding fundamental mechanisms
of Ca2+ channel dysfunction in aging will be vital in developing clinical
treatments for brain senescence, and perhaps for such dementias as
Alzheimer's disease.
通过电压门控Ca 2+通道的Ca 2+内流对于
神经递质释放,突触可塑性,电波形
神经元中基因表达的加工和修饰。 但Ca 2+可以
对神经元也有有害影响;
细胞质Ca 2+浓度导致神经元变性,
最终导致细胞死亡。 这种Ca 2+损伤的积累已经被证明是
被认为是大脑老化和痴呆症的基础。
作为神经元Ca 2+信号传导的主要贡献者,Ca 2+通道
代表了寻找衰老来源的主要潜在目标-
相关的神经元功能障碍。 的确,它是建立在
过去几年,电压门控性Ca 2+通道对
神经元的电活动随着年龄的增长而变化。 的主要目标
项目2是描绘衰老诱导的改变的机制,
脑神经元中电压门控性Ca 2+通道的活性。 研究
该计划旨在实现三个具体目标:
(1)Ca 2+通道的生物物理特性随着衰老而变化?
(2)钙通道活性的衰老依赖性改变是否源于
Ca 2+通道的内在变化?
(3)钙通道活性的衰老依赖性改变是否由
外在影响?
实验方法利用膜片钳技术的特点
电生理技术来检测关键的,但潜在的
微妙的,在老化中的Ca 2+通道行为的变化。 属性可能
改变包括(i)Ca 2+电流的幅度,(ii)电压依赖性
通道激活、失活和失活的效率,(iii)
通道开放,(iv)通过通道的Ca 2+渗透性或(v)
对神经递质受体调节的敏感性。 所有这些
将测量参数并将其作为神经元年龄的函数进行比较。 的
生物物理学和药理学工作将得到以下努力的补充:
确定通道子单元组成是否随老化而改变。 组织和
单细胞mRNA分析将作为实现这一目标的第一步。
结合电生理学和分子生物学的方法将
提供协同努力来追踪Ca 2+通道的起源
与大脑老化有关的功能障碍。 理解基本机制
钙离子通道功能障碍在衰老中的作用将是至关重要的,
治疗大脑衰老,也许还有痴呆症,
老年痴呆症
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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William A Sather其他文献
William A Sather的其他文献
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{{ truncateString('William A Sather', 18)}}的其他基金
Reciprocal Control of Ca2+ Channels by Anchored Protein Kinase A and Calcineurin
锚定蛋白激酶 A 和钙调神经磷酸酶对 Ca2+ 通道的相互控制
- 批准号:
7659662 - 财政年份:2007
- 资助金额:
$ 14.19万 - 项目类别:
Reciprocal Control of Ca2+ Channels by Anchored Protein Kinase A and Calcineurin
锚定蛋白激酶 A 和钙调神经磷酸酶对 Ca2+ 通道的相互控制
- 批准号:
7891245 - 财政年份:2007
- 资助金额:
$ 14.19万 - 项目类别:
Reciprocal Control of Ca2+ Channels by Anchored Protein Kinase A and Calcineurin
锚定蛋白激酶 A 和钙调神经磷酸酶对 Ca2+ 通道的相互控制
- 批准号:
7247405 - 财政年份:2007
- 资助金额:
$ 14.19万 - 项目类别:
Reciprocal Control of Ca2+ Channels by Anchored Protein Kinase A and Calcineurin
锚定蛋白激酶 A 和钙调神经磷酸酶对 Ca2+ 通道的相互控制
- 批准号:
7489305 - 财政年份:2007
- 资助金额:
$ 14.19万 - 项目类别:
ALTERATION OF CALCIUM CHANNEL FUNCTION IN BRAIN AGING
大脑老化过程中钙通道功能的改变
- 批准号:
6311456 - 财政年份:2000
- 资助金额:
$ 14.19万 - 项目类别:
ALTERATION OF CALCIUM CHANNEL FUNCTION IN BRAIN AGING
大脑老化过程中钙通道功能的改变
- 批准号:
6097982 - 财政年份:1999
- 资助金额:
$ 14.19万 - 项目类别:
ALTERATION OF CALCIUM CHANNEL FUNCTION IN BRAIN AGING
大脑老化过程中钙通道功能的改变
- 批准号:
6233994 - 财政年份:1997
- 资助金额:
$ 14.19万 - 项目类别:
STRUCTURAL BASIS OF ION SELECTIVITY IN CALCIUM CHANNELS
钙通道离子选择性的结构基础
- 批准号:
2892079 - 财政年份:1996
- 资助金额:
$ 14.19万 - 项目类别:
Structural Basis of Ion Selectivity in Calciumn Channels
钙通道离子选择性的结构基础
- 批准号:
6328486 - 财政年份:1996
- 资助金额:
$ 14.19万 - 项目类别:
STRUCTURAL BASIS OF ION SELECTIVITY IN CALCIUM CHANNELS
钙通道离子选择性的结构基础
- 批准号:
2274563 - 财政年份:1996
- 资助金额:
$ 14.19万 - 项目类别:
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