Molecular consequences of protein regulation on amyloid plaque burden

蛋白质调节对淀粉样斑块负荷的分子影响

基本信息

批准号：
10461965
负责人：
Timothy W. Rhoads
金额：
$ 15.55万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10461965
关键词：
Acetyl Coenzyme A Acute Disease Affect Age Age-Years Aging Alternative Splicing Alzheimer&apos s Disease Alzheimer&apos s disease pathology Alzheimer&apos s disease risk Amyloid Animals Area Biochemical Pathway Bioinformatics Brain Brain region Caloric Restriction Cerebellum Chronic Disease Clinical Cognition Data Data Set Deposition Development Dietary Intervention Disease Disease Progression Down-Regulation Environment Event Exons Factor Analysis Fasting Future Gliosis Goals Growth Health Health Care Costs Hepatic Human Human Biology Image Immune Impaired cognition Impairment Individual Inflammatory Investigation Lead Link Longevity Macaca mulatta Malnutrition Maps Metabolic Metabolic Pathway Metabolism MicroRNAs Microglia Mitochondria Modeling Molecular Molecular Profiling Monkeys NADH Nerve Degeneration Neurodegenerative Disorders Neurofibrillary Tangles Outcome Pathologic Pathway interactions Pattern Peripheral Persons Phenotype Population Post-Translational Protein Processing Prefrontal Cortex Primates Process Production Protein Isoforms Proteins Proteome Proteomics Public Health RNA Processing Regression Analysis Regulation Research Resected Risk Factors Role Running Sampling Senile Plaques Specimen Stratification Symptoms Temporal Lobe Tissues Translating United States Universities Up-Regulation Wisconsin Work age related aged aging brain base brain metabolism cohort deep sequencing effective therapy experimental study extracellular functional outcomes high risk improved indexing insulin sensitivity insulin signaling molecular scale network models nonhuman primate normal aging novel protein expression recruit response tau Proteins transcriptome sequencing two-photon

项目摘要

PROJECT SUMMARY/ABSTRACT There are almost 6 million individuals with Alzheimer's disease (AD) in the United States, and current predictions suggest over 14 million will be affected by 2050. AD is characterized pathologically by extracellular amyloid plaques and neurofibrillary tangles. However, despite intense research focus on these features we still don't understand the mechanistic basis for cognitive decline or how the plaques and tangles are involved. Age is the largest risk factor for neurodegeneration but the molecular details that connect normal aging and neurodegenerative diseases are unclear. Caloric restriction (CR) without malnutrition delays aging and age- related diseases, including neurodegenerative diseases. A long-running trial of CR in the non-human primate rhesus monkey at the University of Wisconsin-Madison (UW) has confirmed that the benefits of CR translate to primates. Large-scale molecular profiling work to understand the CR response in these animals has revealed general downregulation of growth, immune, and inflammatory pathways and upregulation of metabolic pathways. The hepatic response to short-term CR included a novel role for RNA processing mechanisms such as alternative splicing; changes to exon usage patterns were widespread across the metabolic network recruited by CR. Rhesus monkeys develop plaques spontaneously beginning around their median lifespan of 26 years of age. Banked brain specimens from the UW Aging and CR study therefore represent a significant opportunity to study AD pathology in the context of aging in a highly translatable model. The goal of this study is to use deep sequencing proteomics to investigate the production of protein isoforms from RNA processing events and determine how they correlate with amyloid plaque burden in three brain regions. These data will then be integrated with RNAseq and other data already existing or in the process of being collected from these animals, including tau, peripheral insulin sensitivity, microglia, cognition, metabolism, and other indices, ultimately connecting RNA processing to downstream AD pathology and systemic metabolic health.

项目摘要/摘要美国有近600万患有阿尔茨海默氏病（AD）的人，当前预测表明，超过1400万的影响将受2050年的影响。广告在病理上被细胞外表征淀粉样斑块和神经原纤维缠结。但是，尽管进行了深入的研究，但我们仍然不了解认知能力下降的机理基础，或者如何涉及斑块和缠结。年龄是神经变性的最大危险因素，但是连接正常衰老和的分子细节神经退行性疾病尚不清楚。没有营养不良的热量限制（CR）延迟衰老和年龄相关疾病，包括神经退行性疾病。在非人类灵长类动物中对CR的长期试验威斯康星大学麦迪逊分校（UW）的恒河猴证实，CR的好处转化为灵长类动物。大规模分子分析工作以了解这些动物的CR反应已显示总体下调生长，免疫和炎症途径以及代谢途径的上调。对短期CR的肝反应包括RNA处理机制（例如替代）的新作用剪接；外显子使用模式的变化在CR招募的代谢网络中广泛存在。恒河猴从26年的中位寿命开始自发发展斑块年龄。因此在高度可翻译模型中的衰老背景下研究AD病理学。这项研究的目的是深入测序蛋白质组学以研究RNA处理事件和确定它们与三个大脑区域中淀粉样蛋白斑块负担的相关性。这些数据将是与RNASEQ和其他已经存在的数据集成或从这些动物收集的过程中，包括tau，周围胰岛素敏感性，小胶质细胞，认知，代谢和其他指数，最终将RNA处理连接到下游AD病理学和系统性代谢健康。