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.

项目总结/摘要 衰老过程的特征是学习和记忆的缺陷以及认知能力的普遍下降， 这影响了近33%的70岁以上的美国成年人。老年人的情感和经济负担 照顾者，家庭和纳税人的过程是巨大的，因为预计人口的百分比将 到2050年，65岁及以上的人将从4.1%增加到约20%。的透彻理解 在衰老过程中出错的过程不仅会提供对衰老的机械理解，而且还会 为正在进行的研究提供关键途径，以尽量减少衰老过程对记忆的负面影响。的 衰老的衰弱效应与几个神经过程有关，这些过程在实质性衰老之前发生变化。 在老年人中观察到的组织退化和行为影响。值得注意的是， 神经炎症和突触可塑性已被独立研究，并随着年龄的变化， 海马体，一个主要的大脑区域，参与大多数记忆的形成和储存。小胶质细胞活性 调节神经炎症反应，这与神经元完整性降低有关， 完整性降低，突触强度和学习记忆缺陷。然而，一个链接 神经炎症，研究小胶质细胞活化，和年龄相关的突触可塑性缺陷， 记忆目前还不清楚。胰岛素样生长因子2（Igf 2）是一种蛋白质编码基因，调节 神经炎症、突触可塑性和记忆形成。有趣的是，Igf 2的DNA甲基化增加， 在整个生命周期中发生，这导致Igf 2表达减少。这与年龄有关。 突触可塑性和记忆形成的缺陷，以及炎症反应的增加。但无论 Igf 2 DNA甲基化的增加导致与年龄相关的神经炎症增加， 可塑性和记忆仍然是模棱两可的。这项提案的目的是提供直接证据，将Igf 2 DNA 甲基化增加的神经炎症反应和突触可塑性和记忆的缺陷， 老化过程我们将在两个目标中测试这一点，通过双向操纵Igf 2 DNA甲基化， 使用CRISPR-dCas 9系统的修改版本的海马。目标1将决定Igf 2的影响 甲基化对神经炎症的影响，使用小胶质细胞活化和突触可塑性的常见标志物。目的2 将双向操纵Igf 2甲基化，以了解对老年动物学习和记忆的影响。 使用几个海马依赖记忆任务。总的来说，这些结果将提供洞察力， 通过改变DNA甲基化改变Igf 2表达影响神经炎症的机制 突触可塑性和记忆形成中的年龄相关性反应和缺陷。