Strategies for targeting astrocyte reactivity in Alzheimer's disease and related dementias.

针对阿尔茨海默病和相关痴呆症中星形胶质细胞反应性的策略。

基本信息

批准号：
10845083
负责人：
Christopher Mark Norris
金额：
$ 38.08万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10845083
关键词：
Aging Agreement Alzheimer&apos s Disease Alzheimer&apos s disease related dementia Amyloid Animals Area Astrocytes Behavioral Brain Cells Cerebrovascular Disorders Communities Critiques Data Analyses Dementia Dependovirus Disease model Doxycycline Electrophysiology (science)Experimental Designs Functional disorder Funding Gel Generations Genes Glutamates Goals Human Resources Impairment Individual Insulin Receptor Label Letters Link MMP9 gene Maintenance Measures Medicine Microelectrodes Modeling Molecular Mus Neurons Operative Surgical Procedures Parents Pathology Phenotype Phosphorylation Pilot Projects Positioning Attribute Postdoctoral Fellow Procedures Proto-Oncogene Proteins c-akt Published Comment Quality Control Reagent Receptor Signaling Research Research Design Research Project Grants Role Signal Pathway Signal Transduction Specificity System Techniques Testing Tetracyclines Time Training Transgenic Mice Transgenic Model United States National Institutes of Health Validation Western Blotting biomarker validation brain tissue catalyst college design experimental study human subject in vivo interest knock-down mouse model overexpression pre-clinical programs promoter skills uptake voltage clamp

项目摘要

CORE A Supplement: Abstract-Summary This supplement will operate under the umbrella of Core A of the parent P01 to support the generation of new transgenic mouse lines in which genes-of-interest can either be expressed or knocked down (using doxycycline inducible system) selectively in brain astrocytes. Two lines will be created for each research project (an “Astro- on” and an “Astro-off” line) to target signaling constituents relevant to the reactive astrocyte phenotype and linked to Alzheimer’s disease (AD) or AD-related dementias (ADRDs): MMP9 (Project 1), IRβ (Project 2), SLC1A2 (Project 3), and SUR2B (Project 4). New mouse models will significantly provide greater consistency in terms of (1) the uniformity of astrocytes targeted and (2) the extent of overexpression/knock-down. This advance is expected to reduce mouse-to-mouse variability and increase statistical power. New transgenic models will also streamline study design by eliminating the need for injecting multiple AAV reagents (e.g. one AAV for astrocyte targeting, another AAV for measuring Ca2+) in a single mouse at different time points. This advance will greatly simplify data interpretation, while simultaneously reducing the number of invasive procedures per mouse. Finally, new transgenic models will be readily available to the scientific community to verify our findings or generate new avenues of research, which will promote experimental rigor and further delineate the role of reactive astrocytes in ADRDs.

核心 A 补充：摘要-总结该补充将在母版 P01 的核心 A 的保护下运行，以支持新一代转基因小鼠品系，其中感兴趣的基因可以表达或敲低（使用强力霉素将为每个研究项目选择性地在脑星形胶质细胞中创建两条细胞系（“星形细胞”）。 on”和“Astro-off”线）以靶向与反应性星形胶质细胞表型相关的信号成分并链接阿尔茨海默病 (AD) 或 AD 相关痴呆 (ADRD)：MMP9（项目 1）、IRβ（项目 2）、SLC1A2 （项目 3）和 SUR2B（项目 4）将显着提供更高的一致性。术语（1）靶向星形胶质细胞的均匀性和（2）过度表达/敲低的程度。预计新的转基因模型将减少小鼠之间的变异性并提高统计能力。还通过消除注射多种 AAV 试剂的需要来简化研究设计（例如，一种 AAV 用于星形胶质细胞靶向，另一种用于在不同时间点在单个小鼠中测量 Ca2+ 的 AAV。将大大简化数据解释，同时减少每次侵入性操作的数量最后，科学界将可以随时使用新的转基因模型来验证我们的研究。发现或产生新的研究途径，这将促进实验研究并进一步描绘反应性星形胶质细胞在 ADRD 中的作用。