EXCITATORY TRANSMITTERS, MEMORY, AGING AND DEMENTIA

兴奋性递质、记忆、衰老和痴呆

基本信息

批准号：
6774776
负责人：
JOHN W OLNEY
金额：
$ 149.93万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-02-20 至 2006-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6774776
关键词：
Alzheimer&apos s disease NMDA receptors aging excitatory aminoacid neural degeneration neurotoxins

项目摘要

This is a revised renewal application for a program projects grant entitled Excitatory Transmitters, Memory, Aging and Dementia (ETMAD), which has been funded for 4 years during which we have developed several strong lines of research that will serve as the foundation of this renewal proposal. A central theme of the proposal pertains to a neurodegenerative mechanism, NMDA receptor hypofunction (NRHypo), that we propose may play a key role in Alzheimer's disease (AD). A major emphasis of the proposed research is on testing certain tenets or predictions of the NRHYPO hypothesis. For example, we will induce an NRHYPO neurodegenerative reaction in the brains of transgenic mice to express beta amyloid to determine whether amyloidopathy and the NRHypo degenerative process interact to produce AD-like neuropathological changes and cognition deterioration. We will apply several approaches to address the question whether the neurodegenerative process in AD is mediated by an apoptotic mechanism, as many have proposed, or an excitotoxic mechanism, as our NRHYPO hypothesis proposes. We will explore preliminary evidence suggesting that estrogen may suppress NRHypo neurodegeneration, as it reportedly suppresses the neurodegenerative process in AD. We will follow up experiments to confirm our preliminary evidence to the NRHypo mechanism, and will conduct experiments to confirm our preliminary evidence that non-human primates are susceptible to the NRHypo neurodegenerative mechanism (an issue that currently is in dispute). The ultimate goal of these experiments is to develop a primate model for studying transmitter mechanisms potentially relevant to the pathophysiology of AD. To facilitate research in several projects pertaining to amyloidopathy or apoptosis we proposed to add a new core to the ETMAD program which will maintain a transgenic mouse facility to provide project leaders with transgenic or knockout mice that have genetic alterations relevant to the production or deposition of beta amyloid, or relevant to factors that promote or inhibit expression of apoptotic cell death. This new core facility will replace a prior immunobiology core that has served the ETMAD program well, but is no longer needed.

这是针对计划项目的修订续签申请，名为“兴奋性发射器，记忆，衰老和痴呆症（ETMAD）”，该授权已有4年的资金，在此期间，我们已经开发了多项强大的研究，这些研究将成为该续签建议的基础。该提案的一个核心主题与神经退行性机制NMDA受体功能低下（NRHYPO）有关，我们提出的提议可能在阿尔茨海默氏病（AD）中起关键作用。拟议的研究的主要重点是测试NRHYPO假设的某些原则或预测。例如，我们将在转基因小鼠的大脑中诱导NRHYPO神经退行性反应，以表达β-淀粉样蛋白，以确定淀粉样蛋白病和NRHYPO退化过程是否相互作用以产生AD样神经病理学变化和认知恶化。我们将采用几种方法来解决以下问题，就像许多人所提出的那样，AD中的神经退行性过程是由凋亡机制介导的，还是正如我们的NRHYPO假设所提出的那样。我们将探索初步证据，表明雌激素可以抑制NRHYPO神经变性，因为据报道它抑制了AD中的神经退行性过程。我们将进行跟进实验，以确认我们的初步证据到NRHYPO机制，并将进行实验以确认我们的初步证据，即非人类灵长类动物对NRHYPO神经退行性机制易感（当前正在争论的问题）。这些实验的最终目标是开发一种灵长类动物模型，用于研究与AD的病理生理学有关的发射机机制。为了促进与淀粉样疗法或凋亡有关的多个项目的研究，我们建议在Etmad计划中添加一个新的核心，该计划将维持转基因小鼠设施，以使项目负责人具有与β淀粉样蛋白淀粉样蛋白的生产或沉积相关的转基因或基因敲除小鼠，或与促进抗抑制剂抑制型抗抑制作用的因素相关的遗传变化。这个新的核心设施将取代先前为ETMAD计划服务的免疫生物学核心，但不再需要。

项目成果

期刊论文数量（107）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Excitotoxic versus apoptotic mechanisms of neuronal cell death in perinatal hypoxia/ischemia.

围产期缺氧/缺血时神经元细胞死亡的兴奋毒性与凋亡机制。

DOI：
10.2174/1566524043479158
发表时间：
2004
期刊：
Current molecular medicine
影响因子：
2.5
作者：
Young,Chainllie;Tenkova,Tatyana;Dikranian,Krikor;Olney,JohnW
通讯作者：
Olney,JohnW

The role of T-type calcium channels in peripheral and central pain processing.

DOI：
10.2174/187152706779025490
发表时间：
2006-11
期刊：
CNS & neurological disorders drug targets
影响因子：
0
作者：
S. Todorovic;V. Jevtovic-Todorovic
通讯作者：
S. Todorovic;V. Jevtovic-Todorovic

Serotonergic agents that activate 5HT2A receptors prevent NMDA antagonist neurotoxicity.

激活 5HT2A 受体的血清素能药物可预防 NMDA 拮抗剂的神经毒性。

DOI：
10.1016/s0893-133x(97)00127-9
发表时间：
1998
期刊：
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
影响因子：
0
作者：
Farber,NB;Hanslick,J;Kirby,C;McWilliams,L;Olney,JW
通讯作者：
Olney,JW

Multiple episodes of mild traumatic brain injury result in impaired cognitive performance in mice.

多次轻度创伤性脑损伤会导致小鼠认知能力受损。

DOI：
10.1111/j.1553-2712.2004.tb00761.x
发表时间：
2004
期刊：
Academic emergency medicine : official journal of the Society for Academic Emergency Medicine
影响因子：
0
作者：
Creeley,CatherineE;Wozniak,DavidF;Bayly,PhilipV;Olney,JohnW;Lewis,LawrenceM
通讯作者：
Lewis,LawrenceM

Environmental agents that have the potential to trigger massive apoptotic neurodegeneration in the developing brain.