Core C: Mouse Intervention and Neuropathy Core

核心 C：小鼠干预和神经病变核心

• 批准号: 10333660
• 负责人: Andrei Seluanov
• 金额: $ 40.9万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10333660
• 关键词: Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Animal Experimentation; Animal Housing; Animal Husbandry; Animals; Biological; Biological Assay; Biological Markers; Brain; Brain region; CRISPR/Cas technology; Cell Aging; Chiroptera; Cognition; Collaborations; DNA; Data; Databases; Ensure; Funding; Genes; Genomics; Genotype; Goals; Harvest; Histologic; IACUC; Individual; Inflammaging; Inflammation; Innate Immune Response; Institution; Interferon Type II; Interferons; Intervention; Knockout Mice; L1 Elements; Life; Longevity; Mediating; Modeling; Mole Rats; Mus; Mutate; Mutation; Nerve Degeneration; Neurofibrillary Tangles; Neuropathy; Nucleosides; Pathogenesis; Pathology; Pathway interactions; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Physical Performance; Program Research Project Grants; Protocols documentation; Quality Control; Reporter; Reproducibility of Results; Research Personnel; Retrotransposition; Retrotransposon; Reverse Transcriptase Inhibitors; Rodent; Role; Sampling; Senile Plaques; Signal Transduction; Site; Specimen; Standardization; Sterility; Stimulator of Interferon Genes; Sting Injury; Testing; Tissues; Transgenic Mice; Universities; age related; aged; blind; cognitive performance; cost; experimental study; extracellular; healthspan; improved; inhibitor therapy; mouse model; neuropathology; novel; response; small hairpin RNA; systemic inflammatory response; transcriptomics; treatment effect

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.

小鼠干预和神经病理学核心(核心C)将为该计划项目的研究人员提供 授予(PPG)必要的鼠标模型以实现其特定目标，并将执行鼠标寿命 化验、药物治疗和表征小鼠的表型。这个PPG的首要目标是理解 LINE-1(L1)反转录转座子在年龄相关病理中的作用。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，从而引发全身炎症。堆芯 C有助于说明用核苷逆转录酶抑制物(NRTI)药物治疗小鼠 减轻多种病症，减少炎症。在下一个资金周期中，我们将重点关注 阿尔茨海默病中L1介导性炎症的研究，并确定抑制L1s能否挽救AD 小鼠模型的病理学。核心C具体目标将是：(1)准备和维护机构动物 此PPG内所有项目的关怀和使用委员会协议；(2)生成一个被蝙蝠叮咬的老鼠模型，以 测试抑制的刺痛信号是否减轻AD的病理。这将与Project合作完成 3用CRISPR-Cas9建立小鼠系，其中保守的小鼠Ser358在STING中突变为 艾拉。在所有蝙蝠物种中都发现了Ala358，它能抑制信号，减少炎症。(3)品种 并为项目调查人员维护老鼠；向项目分发老鼠标本。我们将培育出零化者， SIRT6-OE、STING KO、BAT-STING和L1报告小鼠到MAPT和AD的5xFAD小鼠模型用于项目 1和3.从不同年龄的小鼠身上采集包括不同脑区的多个组织，用于 基因组学、转录学和组织学分析。(4)建立和维护项目的小鼠老化群体 1和3.L1基因沉默的小鼠模型将培育成MAPT和5xFAD小鼠模型。 确定鼠标的健康寿命和寿命。(5)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。(六)审查 小鼠在项目1和3中的身体和认知表现。(7)产生具有突变的转基因小鼠 参与转座子监测的基因由项目2确定。包括不同区域的多个组织 大脑将被采集并提供给项目1、2和核心B，用于分析转座子的表达和 发炎。(8)维护所有MICE的数据库，以确保有效地向项目分发材料和数据 调查人员。集中维护鼠群将规范饲养条件、质量控制 和生物样本，用于PPG项目，提高结果的重现性，并允许分析 通过几种化验和项目对同一个体动物进行监测，并尽量减少对动物的使用。