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Core C: Mouse Intervention and Neuropathy Core

核心 C：小鼠干预和神经病变核心

基本信息

批准号：
10581515
负责人：
Andrei Seluanov
金额：
$ 39.8万
依托单位：
BROWN UNIVERSITY
依托单位国家：
美国
项目类别：
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/10581515
关键词：
Affect Age Aging Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease pathology Animal Experimentation Animal Housing Animal Husbandry Animals Biological Biological Assay Biological Markers Brain Brain region Breeding CRISPR/Cas technology Cell Aging Chiroptera Cognition Collaborations Confusion Cytoplasm 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 cellular pathology cognitive performance cost experimental study extracellular healthspan improved inhibitor therapy mouse model neuropathology novel response small hairpin RNA systemic inflammatory response transcriptomics treatment effect

项目摘要

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）将为本项目提供研究人员