INTERDISCIPLINARY APPROACH TO ALZHEIMER DRUG DISCOVERY
阿尔茨海默病药物发现的跨学科方法
基本信息
- 批准号:3091354
- 负责人:
- 金额:$ 44.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1991
- 资助国家:美国
- 起止时间:1991-09-30 至 1996-07-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Alzheimer disease (AD) is a characterized by the deposition of
cerebrovascular and cerebral parenchymal beta/A4-amyloid and progressive
deficiency of effective cholinergic neurotransmission. These two features
are the focus of the proposed Drug Discovery Group.
Investigators in Project 1 will focus on amyloid precursor protein (APP)
processing in brain and cerebral vessels, using synthetic APP peptides and
recombinant APP holoprotein and fragments as APPases will be purified and
characterized. In addition to these enzymological studies, APP processing
will be studied in cultured endothelial cells, smooth muscle cells and
platelets.
Investigators in Project 2 will also use an APP processing assay in intact
cultured cells, rationally choosing compounds based on the cell biology of
APP and screening the compounds for efficacy in regulating APP processing.
Where lead compounds exist, derivatives will be examined in order to
determine structure-activity relationships of the various classes of
compounds. Various host cell systems and an in vivo assay in the brain of
the freely moving rodent will be used as screens. Complementing the cell
biology and biochemical approaches of Projects 1 and 2, investigators in
Project 3 will seek an in vivo model of cerebral amyloidogenesis,
overexpressing in transgenic mice mutant APPs which are likely to favor
amyloidogenesis.
Progressive deficiency in cholinergic neurotransmission is another
prominent feature of AD. Fine molecular and physiological characterization
of the cholinergic system forms another focus of Project 3 and is the
primary focus of Project 4. Newly developed antibodies that differentiate
brain muscarinic receptor subtypes will be used to analyze levels and
distributions of subtypes in the basal forebrain, hippocampus, and
neocortex of aged humans. Also along this line, Project 4 will provide
details regarding the possible therapeutic opportunity offered by
manipulation of galanin, a neuropeptide and functional antagonist of
cholinergic neurotransmission. The preservation in AD of galaninergic
systems, coupled with loss of cholinergic neurons, suggests that galanin
antagonists might be clinically useful.
A Core Facility will serve to provide scientific support to the Projects of
the Drug Discovery Group. Among the functions of the Core will be the
provision of recombinant wildtype and mutant APP and APP fragments,
synthetic peptides, protein purification and sequencing, and industrial
liaison for compound derivatization and large-scale synthesis. Liaison for
legal and patent matters will also be provided as well as the facilitation
of timely communication among all members of the Group.
阿尔茨海默病(AD)是一种特征在于沉积的
脑血管和脑实质β/A4-淀粉样蛋白和进行性
缺乏有效的胆碱能神经传递。 这两个特征
是拟议中的药物发现小组的重点。
项目1的研究人员将专注于淀粉样前体蛋白(APP)
在脑和脑血管中加工,使用合成APP肽,
纯化重组APP全蛋白和作为APP酶的片段,
表征了 除了这些酶学研究,APP加工
将在培养的内皮细胞、平滑肌细胞和
血小板
项目2中的研究者还将使用完整的
培养的细胞,根据细胞生物学合理选择化合物,
APP和筛选化合物在调节APP加工中的功效。
如果存在先导化合物,则将对衍生物进行检查,
确定各种类别的结构-活性关系
化合物. 各种宿主细胞系统和在脑中的体内测定法
自由活动的啮齿动物将被用作屏障。 补充细胞
项目1和2的生物学和生物化学方法,
项目3将寻求脑淀粉样蛋白生成的体内模型,
在转基因小鼠中过表达突变APP,
淀粉样变性
胆碱能神经传递的进行性缺乏是另一个原因
AD的突出特点。 精细的分子和生理表征
胆碱能系统的形成项目3的另一个重点,是
项目四的重点。 新开发的抗体,
脑毒蕈碱受体亚型将用于分析水平,
亚型在基底前脑、海马和
老年人的大脑皮层 此外,沿着这条线,项目4将提供
关于可能的治疗机会的详细信息,
甘丙肽,一种神经肽和功能性拮抗剂,
胆碱能神经传递 甘丙肽能在AD中的保存
系统,再加上胆碱能神经元的损失,表明甘丙肽
拮抗剂可能在临床上有用。
一个核心基金将为以下项目提供科学支持:
药物发现小组 核心的职能包括:
提供重组野生型和突变型APP和APP片段,
合成肽,蛋白质纯化和测序,以及工业
化合物衍生化和大规模合成的联络人。 联络员
法律的和专利事务也将提供以及便利
集团所有成员之间的及时沟通。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
PAUL GREENGARD其他文献
PAUL GREENGARD的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('PAUL GREENGARD', 18)}}的其他基金
MECHANISMS FOR SELECTIVE REGULATION OF GAMMA-SECRETASE (AG09464-21A1 PROJ 2
选择性调节 γ 分泌酶的机制 (AG09464-21A1 项目 2
- 批准号:
8724095 - 财政年份:2013
- 资助金额:
$ 44.9万 - 项目类别:
MECHANISMS FOR SELECTIVE REGULATION OF GAMMA-SECRETASE (AG09464-21A1 PROJ 2
选择性调节 γ 分泌酶的机制 (AG09464-21A1 项目 2
- 批准号:
8735057 - 财政年份:2013
- 资助金额:
$ 44.9万 - 项目类别:
P2 - Role of mGluR5/CK1-CK2/DARPP-32 Pathway in Psychostimulant Effects
P2 - mGluR5/CK1-CK2/DARPP-32 通路在精神兴奋作用中的作用
- 批准号:
8334266 - 财政年份:2011
- 资助金额:
$ 44.9万 - 项目类别:
IDENTIFICATION OF PHOSPHORYLATION SITES ON GLUTAMATE RECEPTOR MGLUR5
谷氨酸受体 MGLUR5 磷酸化位点的鉴定
- 批准号:
8361517 - 财政年份:2011
- 资助金额:
$ 44.9万 - 项目类别:
Identification of Cell Type-Specific Actions of Antipsychotic Drugs
抗精神病药物的细胞类型特异性作用的鉴定
- 批准号:
8151096 - 财政年份:2010
- 资助金额:
$ 44.9万 - 项目类别:
Identification of Cell Type-Specific Actions of Antipsychotic Drugs
抗精神病药物的细胞类型特异性作用的鉴定
- 批准号:
8328723 - 财政年份:2010
- 资助金额:
$ 44.9万 - 项目类别:
Identification of Cell Type-Specific Actions of Antipsychotic Drugs
抗精神病药物的细胞类型特异性作用的鉴定
- 批准号:
7939293 - 财政年份:2010
- 资助金额:
$ 44.9万 - 项目类别:
Identification of Cell Type-Specific Actions of Antipsychotic Drugs
抗精神病药物的细胞类型特异性作用的鉴定
- 批准号:
8475657 - 财政年份:2010
- 资助金额:
$ 44.9万 - 项目类别:
Striatal Cell-specific Analysis of the Molecular Mechanisms of Antipsychotic Drug
抗精神病药物分子机制的纹状体细胞特异性分析
- 批准号:
8150110 - 财政年份:2010
- 资助金额:
$ 44.9万 - 项目类别:
相似海外基金
Development of aggregation inhibition strategy for pathogenic amyloid proteins
致病性淀粉样蛋白聚集抑制策略的开发
- 批准号:
16H06216 - 财政年份:2016
- 资助金额:
$ 44.9万 - 项目类别:
Grant-in-Aid for Young Scientists (A)
Elucidation of the mechanisms on aggregation and toxicity of plant amyloid proteins which are toxic in the presence of metals
阐明在金属存在下有毒的植物淀粉样蛋白的聚集和毒性机制
- 批准号:
23380192 - 财政年份:2011
- 资助金额:
$ 44.9万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Demonstration of the abnormal conformational transition of amyloid proteins and it's application as an early diagnostic tool
淀粉样蛋白异常构象转变的演示及其作为早期诊断工具的应用
- 批准号:
21200072 - 财政年份:2009
- 资助金额:
$ 44.9万 - 项目类别:
Grant-in-Aid for Scientific Research on Innovative Areas (Research a proposed research project)
Metabolism of amyloid proteins and methods for detecting amyloid proteins
淀粉样蛋白的代谢和检测淀粉样蛋白的方法
- 批准号:
21790541 - 财政年份:2009
- 资助金额:
$ 44.9万 - 项目类别:
Grant-in-Aid for Young Scientists (B)
Development of aggregation disrupters for amyloid proteins
淀粉样蛋白聚集破坏剂的开发
- 批准号:
17310132 - 财政年份:2005
- 资助金额:
$ 44.9万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Inhibition of axonal transport of hippocampal neurons by amyloid proteins: relation to Alzheimer's disease
淀粉样蛋白抑制海马神经元轴突运输:与阿尔茨海默病的关系
- 批准号:
11670638 - 财政年份:1999
- 资助金额:
$ 44.9万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
RAB GTPASES AND TRAFFICKING OF BETA AMYLOID PROTEINS
RAB GTP 酶和 β 淀粉样蛋白的贩运
- 批准号:
6149928 - 财政年份:1998
- 资助金额:
$ 44.9万 - 项目类别: