Rehab Therapy Adjunct with a Neurogenic, Mnemoactive, A-Beta-Lowering Compound
含有神经源性、记忆活性、A-β 降低化合物的康复治疗辅助剂
基本信息
- 批准号:8596270
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-03-01 至 2018-02-28
- 项目状态:已结题
- 来源:
- 关键词:AdultAfghanistanAnimal TestingAnti-Anxiety AgentsAnxietyAttenuatedBehavioralBlast CellBlast InjuriesBrainBromodeoxyuridineCellsChronicCognitionCognitiveDiseaseDrug effect disorderEmployee StrikesFutureGeneral AnesthesiaHippocampus (Brain)ImmunoprecipitationIn VitroInjuryIraqLeftLong-Evans RatsMass Spectrum AnalysisMeasuresMetabolismModelingMoodsMusNeuronsPathologyPharmaceutical PreparationsPhenotypePost-Traumatic Stress DisordersPreparationProdrugsProphylactic treatmentProtocols documentationRattusRodent ModelStudy modelsSymptomsTestingTimeTransgenic MiceTraumatic Brain InjuryWararmbasein vivoinhibitor/antagonistmalemorphometrymouse modelneurogenesisnovelpublic health relevanceresearch studytrait
项目摘要
DESCRIPTION (provided by applicant):
Blast related traumatic brain injury (TBI) has been a major cause of injury in the wars in Iraq and
Afghanistan. A striking feature of the mild TBI cases has been the prominent association with post- traumatic stress disorder (PTSD). However, due to the overlapping symptoms distinction between the two disorders has been difficult. Collaborators at our center have characterized a rat model of mTBI in which adult male rats were exposed to repetitive blast injury while under general anesthesia. Blast exposure induced a variety of PTSD-related behavioral traits. In preliminary studies, we have demonstrated that BCI-632/MGS0039 has A¿42-lowering effects in vitro and in vivo as well as pro-cognitive effects in vivo. Based on these results, we predicted
that the group II mGluR inhibitor BCI-632/MGS0039 (or the optimized pro-drug, BCI-838/MGS0210) would attenuate ¿¿ accumulation. In preparation for moving to the rat model, we studied a transgenic mouse model in which we demonstrated not only robust brain A¿-reduction activity, but surprisingly robust anxiolytic activity (as measured by Time in Open Arm, left panel below), pro-cognitive activity (Time Exploring Novel Object, center panel below), and pro-neurogenesis activity (Ki67-positive cells, right panel below). We now propose to move into the blast exposed rat model where we will test the ability of the drug to mitigate the anxiety phenotype in our blast exposed rats through its pro-cognitive, anxiolytic, and hippocampal pro-neurogenic activities. We propose the following specific aims: Specific Aim 1. To evaluate effects of a clinically promising group II mGluR inhibitor (BCI-632/MGS0039) on APP/¿¿ metabolism in vitro using primary neuronal culture in order to establish the mechanism of action of the drug in intact neurons; Specific Aim 2a. To evaluate the in vivo effects in a rodent model of blast-related mTBI/PTSD of the optimized BCI- 838/MGS0210 pro-drug that is metabolized to the active drug BCI-632/MGS0039, a group II mGluR inhibitor. The behavioral profile will include standard Kawarabayashi et al A¿ protocol, including A¿ oligomers and immunoprecipitation-mass spectrometry, following chronic treatment, morphometry of structural pathology, and BrdU and anti-doublecortin analysis for hippocampal neurogenesis. Nontransgenic Long-Evans rats will be studied employing prophylactic and treatment drug protocols before or after exposure of rats to blast TBI. Specific Aim 2b. Pilot experiments will be performed to evaluate the feasibility
of mice as test animals in this model of blast-related mTBI/PTSD. Wildtype and 3xTg mice will be used, in preparation for future projects in which genetically manipulated mice will be exposed to TBI.
描述(由申请人提供):
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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SAMUEL E. GANDY其他文献
SAMUEL E. GANDY的其他文献
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{{ truncateString('SAMUEL E. GANDY', 18)}}的其他基金
Proneurogenic Treatment for Amyloid or Tau-Based Neurodegeneration
针对淀粉样蛋白或 Tau 神经变性的促神经源性治疗
- 批准号:
10378457 - 财政年份:2017
- 资助金额:
-- - 项目类别:
Proneurogenic Treatment for Amyloid or Tau-Based Neurodegeneration
针对淀粉样蛋白或 Tau 神经变性的促神经源性治疗
- 批准号:
9911993 - 财政年份:2017
- 资助金额:
-- - 项目类别:
Rehab Therapy Adjunct with a Neurogenic, Mnemoactive, A-Beta-Lowering Compound
含有神经源性、记忆活性、A-β 降低化合物的康复治疗辅助剂
- 批准号:
9220567 - 财政年份:2014
- 资助金额:
-- - 项目类别:
Rehab Therapy Adjunct with a Neurogenic, Mnemoactive, A-Beta-Lowering Compound
含有神经源性、记忆活性、A-β 降低化合物的康复治疗辅助剂
- 批准号:
9026594 - 财政年份:2014
- 资助金额:
-- - 项目类别:
Rehab Therapy Adjunct with a Neurogenic, Mnemoactive, A-Beta-Lowering Compound
含有神经源性、记忆活性、A-β 降低化合物的康复治疗辅助剂
- 批准号:
8825927 - 财政年份:2014
- 资助金额:
-- - 项目类别:
Model for SorCS1-mediated Diabetes with Dementia
SorCS1 介导的糖尿病伴痴呆模型
- 批准号:
8599496 - 财政年份:2012
- 资助金额:
-- - 项目类别:
Generation and Characterization of Alzheimer Brain Cells
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- 批准号:
8370239 - 财政年份:2012
- 资助金额:
-- - 项目类别:
Model for SorCS1-mediated Diabetes with Dementia
SorCS1 介导的糖尿病伴痴呆模型
- 批准号:
8788636 - 财政年份:2012
- 资助金额:
-- - 项目类别:
Model for SorCS1-mediated Diabetes with Dementia
SorCS1 介导的糖尿病伴痴呆模型
- 批准号:
8295466 - 财政年份:2012
- 资助金额:
-- - 项目类别:
Model for SorCS1-mediated Diabetes with Dementia
SorCS1 介导的糖尿病伴痴呆模型
- 批准号:
8411973 - 财政年份:2012
- 资助金额:
-- - 项目类别:
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