Non-coding RNAs in resilience to Alzheimer’s Disease

非编码 RNA 有助于抵抗阿尔茨海默病

• 批准号: 10666167
• 负责人: Winston Alexander Hide
• 金额: $ 86.25万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2028-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10666167
• 关键词: 3-Dimensional; Address; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease related dementia; Amyloid beta-Protein; Basic Science; Biological; Biological Models; Biology; Brain; Brain region; CRISPR interference; Cell Culture Techniques; Cell Line; Cell Survival; Cell model; Cell physiology; Cells; Cellular Stress; Code; Cognition; Cognitive; Compensation; Complex; Data; Dementia; Disease; Elderly; Future; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic Transcription; Goals; Health; Homeostasis; Human; Impaired cognition; In Situ; In Vitro; Individual; Intervention; Life; Link; Mediating; MicroRNAs; Modeling; Molecular; Neurites; Neurofibrillary Tangles; Neuroglia; Neurons; Organoids; Pathology; Pathway interactions; Persons; Pharmaceutical Preparations; Phenotype; Play; Population; Process; RNA; Regulation; Regulator Genes; Role; Serum; Solid; Systems Biology; Technology; Testing; Therapeutic; Tissues; Translational Research; Tropism; Untranslated RNA; biological adaptation to stress; brain tissue; cell dimension; comparative; exosome; human subject; in silico; induced pluripotent stem cell; knock-down; loss of function; nanoparticle; neuroinflammation; neuropathology; neuroprotection; novel; prevent; promote resilience; rare variant; resilience; resilience factor; response; small hairpin RNA; therapeutic biomarker; therapeutic target; tool; transcriptomics

Non-coding RNAs in resilience to Alzheimer’s Disease: PI’s Hide, Kim, Slack Summary (30 lines) This proposal is a response to RFA-AG-23-010 Noncoding RNAs in Alzheimer’s Disease and Related Dementias. The overarching goal of the proposed study is to define and characterize key noncoding RNA (ncRNA) regulators of mechanisms of biological resilience against cognitive loss in Alzheimer’s disease (AD). An individual who is resilient to AD-related neuropathology and does not show cognitive decline despite the presence of AD-related neuropathology will be less likely to develop dementia later in life. A striking natural subpopulation of the elderly remain cognitively intact while controlling or compensating for AD-related pathology. As of yet, drug interventions targeting specific AD-related pathologies, such as β-amyloid, neurofibrillary tangles, or neuroinflammation, have been largely ineffective in controlling AD pathology-related cognitive decline - AD related dementia (AD/ADRD). A compelling alternative is to find ways to enhance resilience against AD/ADRD. During aging, the fidelity of transcriptional regulatory processes declines with associated loss of function and cognitive decline. Proper coding and noncoding gene expression regulation is critical for maintaining homeostasis and preventing disease processes. ncRNAs are increasingly recognized as potent, highly specific regulators of gene expression at all levels. ncRNAs play a critical role in cell stress response. Given the large number of miRNA and lncRNA genes and gene/lncRNA/miRNA interactions and the overarching role of these RNAs in normal processes of the cell, ncRNAs have enormous potential not only as therapeutic targets and biomarkers for the pathologies of aging, but also as key intermediate mechanism markers - helping define mechanisms of disease response that they regulate. We will perform the first study that systematically identifies and characterizes novel ncRNA-regulated resilience mechanisms in AD; derived from human subject data. This project will establish a systematic framework for identification of resilience processes, to explain the roles of ncRNAs in resilience to AD at the cellular and molecular level. Our comprehensive approach will uncover the role of ncRNA factors of resilience to cognitive decline. Using systematic analysis of cognitively resilient populations and powerful tools that identify resilience lncRNAs and miRNAs, we will identify and characterize the interactions, functions and targets of prioritized resilience- associated ncRNAs in our in vitro neuronal/glial cell culture models and advanced three-dimensional (3D) human neural cell culture models of AD. The team brings together broad and deep inter-disciplinary expertise in ncRNA biology, systems biology and Alzheimer’s disease pathology, with a solid basic and translational science background to address understanding of ncRNA in aging (Slack), ncRNA targeting (Vlachos), systems biology of complex disease (Hide) and expertise in 3D AD model systems (Kim) and AD (Tanzi).

非编码RNA对阿尔茨海默病的韧性：Pi‘s Hide，Kim，Slack 摘要(30行) 这项建议是对阿尔茨海默病及其相关疾病中非编码RNA的响应 痴呆症。这项拟议研究的首要目标是定义和表征关键的非编码RNA (NcRNA)阿尔茨海默病(AD)生物弹性机制的调节。 对阿尔茨海默病相关的神经病理有恢复能力并且没有表现出认知能力下降的人，尽管 存在与AD相关的神经病理将不太可能在以后的生活中发展为痴呆症。一种惊人的自然 老年人亚群在控制或补偿AD相关疾病时保持认知完好无损 病理学。到目前为止，针对特定AD相关病理的药物干预，如β-淀粉样蛋白， 神经原纤维缠结，或神经炎症，在控制与AD病理相关的方面基本上无效 认知衰退--AD相关痴呆(AD/ADRD)。一个令人信服的替代方案是找到方法来增强 对AD/ADRD的恢复能力。在衰老过程中，转录调控过程的保真度随着 相关的功能丧失和认知能力下降。正确的编码和非编码基因表达调控是 对维持动态平衡和预防疾病进程至关重要。越来越多的人认识到ncRNAs 作为所有水平的基因表达的高效、高度特异的调节器。NcRNAs在细胞应激中起关键作用 回应。考虑到大量的miRNA和lncRNA基因以及基因/lncRNA/miRNA的相互作用 这些RNA在细胞正常过程中的重要作用，ncRNAs不仅具有巨大的潜力 作为衰老病理的治疗靶点和生物标志物，也是关键的中间机制 标记物--帮助定义它们所调控的疾病反应机制。我们将进行第一项研究 系统地识别和表征了AD中ncRNA调节的新的复原力机制；衍生 来自人类受试者的数据。该项目将建立一个确定复原力的系统框架 过程，以在细胞和分子水平上解释ncRNAs在AD复原力中的作用。我们的 综合的方法将揭示ncRNA因素对认知衰退的弹性作用。vbl.使用 对认知有弹性的种群进行系统分析，并使用强大的工具来识别弹性lncRNA和 MiRNAs，我们将识别和表征优先恢复能力的相互作用、功能和目标- 我们的体外神经元/神经胶质细胞培养模型和先进的三维(3D)模型中的相关ncRNA 人阿尔茨海默病神经细胞培养模型。该团队汇集了广泛而深厚的跨学科专业知识。 在核糖核酸生物学、系统生物学和阿尔茨海默病病理学方面，具有扎实的基础和翻译 科学背景以解决对ncRNA在衰老中的理解(Slack)、ncRNA靶向(Vlachos)、 复杂疾病的系统生物学(HIDE)以及3D AD模型系统(KIM)和AD(TANZI)的专业知识。