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：抽象 - 夏姆该补充剂将在父级P01的核心A的伞下运行，以支持新的生成转基因小鼠线，其中利益基因可以表达或敲低（使用强力霉素诱导系统）在大脑星形胶质细胞中有选择性。每个研究项目都会创建两条线（“ astro- 在“上”和“星空”线）以构成与反应性星形胶质细胞表型相关的靶向信号。阿尔茨海默氏病（AD）或与AD相关的痴呆症（ADRDS）：MMP9（项目1），IRβ（项目2），SLC1A2 （项目3）和SUR2B（项目4）。新的鼠标模型将显着提供更大的一致性（1）靶向星形胶质细胞的均匀性和（2）过表达/敲低的程度。这进展预计将减少鼠标到小鼠的变异性并增加统计功率。新的转基因模型将同样可以通过消除注入多个AAV试剂的需求来简化研究设计（例如星形胶质细胞靶向，在不同时间点中测量单个鼠标中的Ca2+）的另一个AAV。这进展将大大简化数据解释，同时减少每个侵入性过程的数量老鼠。最后，科学界将很容易获得新的转基因模型，以验证我们的调查结果或产生了新的研究途径，这将促进实验性严格，并进一步描述反应性星形胶质细胞在ADRD中的作用。