Testing Direct Effects of mGluR5 Inhibition in an Alzheimer's Disease Mouse Model

在阿尔茨海默病小鼠模型中测试 mGluR5 抑制的直接效果

基本信息

批准号：
8741913
负责人：
CARA JEAN WESTMARK
金额：
$ 18.81万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-30 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8741913
关键词：
Acetylcholine Adult Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Amyloid beta-Protein Precursor Animals Anxiety Attenuated Behavioral Biological Availability Biological Markers Brain region Cancer Therapy Evaluation Program Cholinesterase Inhibitors Clinical Data Clinical Trials Cognitive Dementia Dendrites Dendritic Spines Development Disease Disease Progression Drug Industry Drug Kinetics Etiology Family Fragile X Mental Retardation Protein Fragile X Syndrome Genes Glutamates Goals Grant Half-Life Human Immunization Laboratories Learning Legal patent Length Mediating Memantine Memory Memory impairment Messenger RNA Metabotropic Glutamate Receptors Modeling Mus Mutation N-Methyl-D-Aspartate Receptors Nerve Degeneration Neurons Oral Orphan Drugs Outcome Pathology Peptides Pharmaceutical Preparations Phase Phase II Clinical Trials Phenotype Play Process Production RNA-Binding Proteins Receptor Signaling Rodent Model Role Seizures Severity of illness Symptoms Synapses Synaptic plasticity Testing Therapeutic Therapeutic Intervention Transgenic Mice Translations aged density drug discovery efficacy testing familial Alzheimer disease fenobam genetic manipulation improved in vivo kindred memory process metabotropic glutamate receptor type 1 mouse model mutant nervous system disorder neuron loss neurotoxic novel postsynaptic pre-clinical presenilin protein expression public health relevance receptor research study response synaptic function synaptogenesis tau Proteins theories treatment strategy

项目摘要

DESCRIPTION (provided by applicant): This project explores the hypothesis that mGluR5 antagonists are a viable therapeutic strategy to treat Alzheimer's disease. Findings from our laboratory indicate that mGluR5 antagonists reduce the expression of Abeta in mouse models of Alzheimer's disease. Our goal in this R21 application, in response to PAS-10-151 "Grants for Alzheimer's Disease Drug Discovery", is to provide in vivo proof-of-concept evidence that mGluR5 antagonists are a viable therapeutic strategy to reduce Abeta and ensuing learning and memory deficits in TgCRND8 mice, a mouse model of Alzheimer's disease. Specifically, we will test the efficacy of the mGluR5 antagonist fenobam, which is an off-patent, orphan drug that has passed Phase I and Phase II clinical trials and that could be repurposed for the treatment of AD, with CTEP, an experimental negative allosteric modulator of mGluR5 with a long half-life and high oral bioavailability. In aggregate, these studies will provide pre-clinical data on the efficay of fenobam and CTEP in regards to AD biomarkers and cognitive phenotypes in WT and TgCRND8 littermates.

描述（由申请人提供）：该项目探讨了MGLUR5拮抗剂是治疗阿尔茨海默氏病的可行治疗策略的假设。我们实验室的发现表明，MGLUR5拮抗剂在阿尔茨海默氏病小鼠模型中降低了Abeta的表达。我们在此R21应用中的目标是回应PAS-10-151“阿尔茨海默氏病药物发现的赠款”，是为了提供体内概念证据证据，即MGLUR5拮抗剂是一种可行的治疗策略，可减少Abeta，并在TGCRND8 MITE中进行TGCRND8小鼠的学习和记忆力，而Alzheimers e Alzheimerise sape tgcrnd8 Miete in tgcrnd8小鼠。具体来说，我们将测试MGLUR5拮抗剂Fenobam的功效，该拮抗剂Fenobam是一种过分的孤儿药，已经通过了I期和II期临床试验，可以用CTEP治疗AD，CTEP，CTEP，一种实验性的MGLUR5负相变的MGLUR5，具有长期的Half Life and Life和Higal Bikioavavaimability。总体而言，这些研究将提供有关Fenobam和CTEP在WT和TGCRND8同窝仔的AD生物标志物和认知表型方面的效率的临床前数据。