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

核心A补充：摘要-总结 该补充将在母公司P01的核心A的保护伞下运行，以支持新一代 转基因小鼠系，其中感兴趣的基因可以被表达或敲低（使用强力霉素 诱导系统）选择性地在脑星形胶质细胞中。每个研究项目将创建两条线（一条“天文- 和“Astro-off”线）靶向与反应性星形胶质细胞表型相关的信号传导成分， 阿尔茨海默病（AD）或AD相关痴呆（ADRD）：MMP 9（项目1）、IRβ（项目2）、SLC 1A 2 （项目3）和SUR 2B（项目4）。新的小鼠模型将显著提供更大的一致性， （1）所靶向的星形胶质细胞的均匀性和（2）过表达/敲低的程度。这一进步 预期可降低小鼠间变异性并增加统计功效。新的转基因模型将 还通过消除注射多种AAV试剂的需要（例如，一种AAV用于 星形胶质细胞靶向，另一种用于测量Ca 2+的AAV）。这一进步 这将大大简化数据解释，同时减少每例患者的侵入性手术数量。 老鼠.最后，新的转基因模型将随时提供给科学界，以验证我们的 研究结果或产生新的研究途径，这将促进实验的严谨性，并进一步阐明 反应性星形胶质细胞在ADRD中的作用。

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.