Aplysia as a test of the viral theory of aging

海兔作为病毒衰老理论的检验

• 批准号: 10289803
• 负责人: LYNNE A FIEBER
• 金额: $ 25.89万
• 依托单位: UNIVERSITY OF MIAMI ROSENTEIL SCHOOL
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-05-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10289803
• 关键词: Address; Affect; Afferent Neurons; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease related dementia; Amyloid; Amyloid beta-Protein; Aplysia; Aplysia species; Behavioral; Biological Models; Biomedical Research; Brain; Caenorhabditis elegans; California; Cell model; Cell physiology; Cells; Cessation of life; Chronic; Communities; Complex; Data; Data Set; Databases; Dementia; Development; Disease; Disease Progression; Dose; Down-Regulation; Drosophila genus; Education; Etiology; Exhibits; Genes; Genetic Transcription; Genome; Goals; Grant; Guilt; Human; Immune; Immune response; Infection; Invertebrates; Investigation; Investments; Laboratories; Learning; Link; Mammals; Maps; Memory; Messenger RNA; Methods; Modeling; Nerve Degeneration; Nervous system structure; Neurologic; Neurons; Orthologous Gene; Outcome; Parents; Phenotype; Prefrontal Cortex; Process; Research; Research Personnel; Resources; Role; Severities; Statistical Models; Syndrome; System; Techniques; Testing; Therapeutic; Transcript; Transfection; Universities; Up-Regulation; Viral; Viral Load result; Virus; Virus Diseases; antimicrobial peptide; base; biological adaptation to stress; brain dysfunction; cognitive change; design; differential expression; excitatory neuron; falls; improved; model development; nervous system infection; neural model; neurophysiology; normal aging; novel; parent grant; programs; protein aggregation; response; senescence; single-cell RNA sequencing; tau Proteins; tau mutation; theories; tool; transcriptome; transcriptome sequencing; transcriptomics

Alzheimer’s Disease (AD) is a complex, chronic syndrome, likely with multiple underlying etiologies. In spite of considerable investment, most therapeutic strategies tested to date have had disappointing outcomes. This suggests the need to explore additional model systems that will allow different approaches to testing current as well as alternative hypotheses about the etiology of AD and its related dementias (ADRD). The sea hare Aplysia californica (Aplysia) is a widely used model of neuronal cell function and the cellular basis of learning and memory. Aplysia exhibits a predictable aging process leading to senescence and death at age 12 months. Our research has shown that Aplysia is an excellent model of aging wherein behavioral, neurophysiological, and transcriptomic analyses can be combined to understand fundamental processes in nervous system aging. Aplysia and other mollusks have been demonstrated to be evolutionarily closer to mammals than ecdysozoan models of AD (Drosophila and C. elegans). We recently demonstrated that Aplysia expresses a variety of genes orthologous to those implicated in AD progression, underscoring the relevance of this model. Moreover, a natural viral infection has been identified in the nervous system of Aplysia, which may be similar to viral infections of the human brain that recently have been suggested to contribute to the onset of the amyloid proteinopathies that define AD. Recent data from our laboratory also show that viral load increases with age and may affect the aging process. Here we propose a 1-year study to test the aging Aplysia model as a model of virus-induced AD and ADRD, primarily by employing new models to analyze the Aplysia nervous system transcriptome in the context of a naturally occurring viral infection that increases with age. We will also leverage the large neurons of Aplysia to perform single cell transcriptomics in a single cell model of the effects of human mutant tau protein. This approach is based on many unique advantages of the Aplysia system for these studies. We will explore development of this model through three proposed aims: (1) Transfection of buccal S cluster sensory neurons (BSC) with mutant tau mRNA combined with single cell RNA sequencing will elucidate whether these transfections mimic the transcriptional phenotype of AD. (2) We will use an age-viral load covariate statistical model to compare low vs. high viral load Aplysia sensory neuron RNA sequencing data from our current datasets to determine the effects of viral load on the aging transcriptome and as a model for virus-induced sporadic AD. (3) We will identify potential novel antimicrobial peptides (AMP) in yet to be annotated Aplysia transcripts using motif identification-based methods to identify AMP with the capacity to form protein aggregates in a manner similar to that of amyloid beta (Aβ) and thus serve as more informed candidates for models of Aβ’s AMP-like activity. The proposed research provides a targeted and unique opportunity to evaluate the potential usefulness of Aplysia as a model of AD and ADRD.

阿尔茨海默氏病（AD）是一种复杂的慢性综合征，可能具有多种潜在病因。尽管 迄今为止，大量投资，大多数经过测试的治疗策略令人失望。这 提出需要探索其他模型系统的需要，该系统将允许不同的方法测试电流 以及关于AD病因及其相关痴呆症（ADRD）的替代假设。海野兔 Aplysia califorchica（Aplysia）是一种广泛的神经元细胞功能的模型，是学习的细胞基础 和内存。 Aplysia表现出可预测的衰老过程，导致12个月的感受和死亡。 我们的研究表明，Aplysia是一种出色的衰老模型，其中行为，神经生理学， 可以将转录组分析组合在一起，以了解神经系统衰老的基本过程。 与ecdysozoan相比 AD模型（果蝇和秀丽隐杆线虫）。我们最近证明了Aplysia表达了各种各样的 基因与AD进展中暗示的基因直系同源，强调了该模型的相关性。而且， 在垂体的神经系统中已经鉴定出一种天然病毒感染，这可能与病毒相似 最近有人建议对人脑的感染有助于淀粉样蛋白的发作 定义AD的蛋白质病。我们实验室的最新数据还表明，病毒负荷随着年龄的增长而增加 并可能影响衰老过程。在这里，我们提出了一项为期1年的研究，以测试衰老的Aplysia模型作为模型 病毒引起的AD和ADRD，主要是通过使用新模型来分析Aplysia神经系统 在自然发生的病毒感染的情况下，转录组随着年龄的增长而增加。我们也会 利用大型Aplysia神经元在效应的单个细胞模型中执行单细胞转录组学 人突变tau蛋白。这种方法基于Aplysia系统的许多独特优势 这些研究。我们将通过提出的三个目标探索该模型的开发：（1）转染 与突变体tau mRNA与单细胞RNA测序结合的颊S簇感觉神经元（BSC）将会 阐明这些转染是否模仿AD的转录表型。 （2）我们将使用年龄段 负载协变量统计模型比较低病毒载脂峰感觉神经元RNA测序 来自我们当前数据集的数据，以确定病毒载荷对老化转录组的影响以及作为模型 用于病毒诱导的零星AD。 （3）我们将确定潜在的新型抗菌胡椒（AMP） 使用基于基准识别的方法识别具有形成能力的AMP的注释的Aplysia转录本 蛋白质聚集物的方式与淀粉样蛋白β（Aβ）相似，因此作为更知情的 Aβ类似AMP活性模型的候选者。拟议的研究提供了有针对性的独特 评估Aplysia作为AD和ADRD模型的潜在实用性的机会。