IGF2 regulation of microglia and synaptic function during aging

IGF2 对衰老过程中小胶质细胞和突触功能的调节

• 批准号: 10703353
• 负责人: TIMOTHY JOSEPH JAROME
• 金额: $ 22.79万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10703353
• 关键词: Adult; Affect; Age; Age-associated memory impairment; Aging; American; Animals; Behavioral; Behavioral Paradigm; Biological; Brain; Brain region; Caregivers; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Collaborations; Control Groups; DNA Methylation; DNA Modification Methylases; DNMT3a; Deterioration; Development; Dorsal; Electrophysiology (science); Emotional; Epigenetic Process; Family; Financial Hardship; Functional disorder; Gene Silencing; Genes; Genetic Techniques; Genetic Transcription; Goals; Guide RNA; Hippocampus; Human; IGF2 gene; Impairment; Individual; Inflammatory; Inflammatory Response; Infusion procedures; Injections; Insulin-Like Growth Factor II; Knowledge; Learning; Link; Literature; Location; Long-Term Potentiation; Longevity; Measures; Mediating; Mediator; Memory; Memory Loss; Memory impairment; Mental disorders; Methylation; Microglia; Modeling; Molecular Biology; Neurodegenerative Disorders; Neurologic Process; Neurons; Older Population; Physiological; Plasmids; Population; Positioning Attribute; Process; Proteins; Rattus; Regulation; Reporting; Research; Rodent; Role; Synapses; Synaptic plasticity; System; Testing; Therapeutic; Tissues; Translational Research; age effect; age related; aged; cognitive ability; cognitive performance; cohort; conditioned fear; cytokine; demethylation; design; experience; experimental study; improved; in vivo; insight; long term memory; middle age; mild cognitive impairment; nervous system disorder; neuroinflammation; new technology; normal aging; novel; novel therapeutic intervention; prevent; promoter; research study; response; synaptic function; therapeutic development; translational potential; young adult

Project Summary/Abstract The aging process is characterized by deficits in learning and memory and a general decline in cognitive abilities, which affects nearly 33% of U.S. adults over the age of 70. The emotional and financial burden of the aging process on caregivers, family, and taxpayers is substantial, as the projected percentage of the population will increase from 4.1% to approximately 20% by 2050 for individuals 65 and older. A thorough understanding of the processes that go awry during aging will not only provide a mechanistic understanding of aging, but will also provide key avenues for ongoing research to minimize the negative effects of the aging process on memory. The debilitating effects of aging have been linked to several neurological processes that change prior to substantial tissue deterioration and behavioral effects observed in older populations. Notably, alterations in neuroinflammation and synaptic plasticity have been independently studied and change with age in the hippocampus, a major brain region involved in the formation and storage of most memories. Activity of microglia regulate neuroinflammatory responses, which has been linked to decreased neuronal integrity, and as neuronal integrity decreases, deficits in synaptic strength and learning and memory have been reported. However, a link between neuroinflammation, studied with microglia activation, and age-related deficits in synaptic plasticity and memory are currently unclear. Insulin like growth factor 2 (Igf2) is a protein encoding gene that regulates neuroinflammation, synaptic plasticity, and memory formation. Interestingly, increased DNA methylation of Igf2 occurs over the course of the lifespan, which leads to decreased Igf2 expression. This coincides with age-related deficits in synaptic plasticity and memory formation, and increases in inflammatory responses. However, whether increased Igf2 DNA methylation leads to age-related increases in neuroinflammation and decreases in synaptic plasticity and memory remain equivocal. The goal of this proposal is to provide direct evidence linking Igf2 DNA methylation to increased neuroinflammatory responses and deficits in synaptic plasticity and memory during the aging process. We will test this in two aims by bidirectionally manipulating Igf2 DNA methylation in the hippocampus using a modified version of the CRISPR-dCas9 system. Aim 1 will determine the impact of Igf2 methylation on neuroinflammation, using common markers of microglia activation and synaptic plasticity. Aim 2 will bidirectionally manipulate Igf2 methylation to understand the effects on learning and memory in aged animals using several hippocampal dependent memory tasks. Collectively, these results will provide insight for a mechanism through which changes in Igf2 expression via altered DNA methylation influence neuroinflammatory responses and age-related deficits in synaptic plasticity and memory formation.

项目摘要/摘要 衰老过程的特征是学习和记忆缺陷以及认知能力的普遍下降， 影响70岁以上美国成年人的近33％。衰老的情感和经济负担 护理人员，家庭和纳税人的流程很大，因为预计人口的百分比将 65岁及以上的个体，到2050年，从4.1％增加到约20％。对 在衰老期间出现问题的过程不仅会提供对衰老的机械理解，而且还将 提供持续研究的关键途径，以最大程度地减少衰老过程对记忆的负面影响。这 衰老的衰老效应已与几种在实质性之前发生变化的神经系统相关联 在较老的人群中观察到的组织恶化和行为效应。值得注意的是，改变 神经炎症和突触可塑性已被独立研究，随着年龄的变化而改变 海马，这是一个主要的大脑区域，涉及大多数记忆的形成和存储。小胶质细胞的活性 调节神经炎症反应，与神经元完整性降低有关 完整性降低，突触强度的缺陷以及学习和记忆的报道。但是，一个链接 在神经炎症之间，用小胶质细胞激活进行研究，并在突触可塑性中与年龄相关的缺陷 内存目前尚不清楚。胰岛素类似生长因子2（IGF2）是一种调节的蛋白质编码基因 神经炎症，突触可塑性和记忆形成。有趣的是，IGF2的DNA甲基化增加 发生在整个寿命过程中，从而导致IGF2表达降低。这与年龄有关 突触可塑性和记忆形成的缺陷，并增加炎症反应。但是，是否 IGF2 DNA甲基化增加导致与年龄相关的神经炎症增加，突触减少 塑性和记忆仍然是模棱两可的。该提案的目的是提供与IGF2 DNA联系的直接证据 甲基化以增加神经炎症反应以及突触可塑性和记忆力缺陷 衰老过程。我们将通过双向操纵IGF2 DNA甲基化在两个目标中进行测试 海马使用CRISPR-DCAS9系统的修改版本。 AIM 1将确定IGF2的影响 使用小胶质细胞活化和突触可塑性的公共标记对神经炎症的甲基化。目标2 双向操纵IGF2甲基化以了解对年龄动物的学习和记忆的影响 使用几个海马依赖的内存任务。总的来说，这些结果将为A提供见识 通过改变DNA甲基化影响神经炎症的机制，IGF2表达的变化 突触可塑性和记忆形成中的反应和与年龄相关的缺陷。