Core C: Mouse Intervention and Neuropathy Core

小鼠干预和神经病理学核心（核心C）将为本计划项目的研究者提供 格兰特（PPG）与小鼠模型，以实现其特定的目标，并将执行小鼠寿命 测定、药物治疗和表征小鼠表型。本PPG的首要目标是了解 LINE-1（L1）反转录转座子在年龄相关疾病中的作用。在当前的融资周期中，我们发现 L1通过cGAS-STING途径诱导干扰素反应而引发全身性炎症。核心 C有助于显示用核苷逆转录酶抑制剂（NRTI）药物治疗小鼠 缓解多种病理并减少炎症。在下一个融资周期，我们将重点关注 L1介导的炎症在阿尔茨海默病中的作用，并确定抑制L1是否能挽救AD 小鼠模型中的病理学。核心C具体目标将是：（1）准备和维护实验动物 本PPG内所有项目的护理和使用委员会方案;（2）生成“蝙蝠-STING”小鼠模型， 测试抑制的STING信号传导是否加重AD病理。这将与项目合作完成。 通过使用CRISPR-Cas9制备小鼠系，其中STING中的保守小鼠Ser 358突变为 阿拉巴马州Ala 358存在于所有蝙蝠物种中，并导致信号传导减弱和炎症减少。(3)品种 并为项目研究人员维护小鼠;向项目分发小鼠标本。我们会培育出歼灭者 SIRT 6-OE、STING KO、bat-STING和L1报告小鼠与AD的MAPT和5xFAD小鼠模型的比较 1和3.将从不同年龄的小鼠中收获包括脑的不同区域的多种组织，以用于 基因组学、转录组学和组织学分析。(4)为项目建立和维护小鼠老化菌落 1和3.将具有遗传沉默的L1元件的小鼠模型培育成MAPT和5xFAD小鼠模型。 确定小鼠的健康寿命和寿命。(5)用NRTI（FTC）治疗MAPT和5xFAD小鼠模型， 项目1和3，并确定治疗对小鼠寿命/健康寿命和认知的影响。(6)审查 项目1和项目3的小鼠身体和认知表现。(7)产生具有以下突变的转基因小鼠： 参与转座子监测的基因由项目2确定。多种组织，包括 收获脑并提供给项目1、2和核心B用于分析转座子表达， 炎症(8)维护所有mice的数据库，确保有效地将材料和数据分发给项目 investigators.保持集中的啮齿动物群落将标准化饲养条件，质量控制 和生物样品，用于PPG项目，提高结果的再现性，并允许分析 通过几个试验和项目对同一个体动物进行检测，并尽量减少动物使用。

The Mouse Intervention and Neuropathology Core (Core C) will provide investigators of this Program Project Grant (PPG) with mouse models necessary to achieve their specific aims, and will perform mouse lifespan assays, drug treatments and characterize mouse phenotypes. The overarching goal of this PPG is to understand the role of LINE-1 (L1) retrotransposons in age-related pathologies. In the current funding cycle, we discovered that L1s trigger systemic inflammation by inducing an interferon response via the cGAS-STING pathway. Core C was instrumental in showing that treatment of mice with nucleoside reverse transcriptase inhibitor (NRTI) drugs alleviates multiple pathologies and reduces inflammation. In the next funding cycle, we will focus on the role of L1-mediated inflammation in Alzheimer’s disease and determine whether inhibition of L1s rescues AD pathology in mouse models. Core C Specific Aims will be to: (1) Prepare and maintain the Institutional Animal Care and Use Committee protocols for all projects within this PPG; (2) Generate a ‘bat-STING’ mouse model to test whether dampened STING signaling alleviates AD pathology. This will be done in collaboration with Project 3 by making a mouse line, using CRISPR-Cas9, in which the conserved mouse Ser358 in STING is mutated to Ala. Ala358 is found in all bat species and results in dampened signaling and reduced inflammation. (3) Breed and maintain mice for project investigators; distribute mouse specimens to the projects. We will breed Annihilator, SIRT6-OE, STING KO, bat-STING and L1 reporter mice to MAPT and 5xFAD mouse models of AD for Projects 1 and 3. Multiple tissues including different regions of the brain will be harvested from mice of different ages for genomic, transcriptomic, and histological analyses. (4) Establish and maintain mouse aging colonies for Projects 1 and 3. Mouse models with genetically silenced L1 elements will be bred to MAPT and 5xFAD mouse models. Determine mouse healthspan and lifespan. (5) Treat MAPT and 5xFAD mouse models with NRTIs (FTC) for Projects 1 and 3 and determine the effect of the treatment on mouse life/health span and cognition. (6) Examine mouse physical and cognitive performance for Projects 1 and 3. (7) Generate transgenic mice with mutations in genes involved in transposon surveillance identified by Project 2. Multiple tissues including different regions of the brain will be harvested and provided to Projects 1, 2 and Core B for analysis of transposon expression and inflammation. (8) Maintain a database of all mice to ensure efficient distribution of materials and data to project investigators. Maintaining the centralized rodent colonies will standardize husbandry conditions, quality control and biological samples for use across the PPG projects, improve reproducibility of results, and allow the analysis of the same individual animals by several assays and projects, as well as minimize animal use.