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).

对阿尔茨海默氏病的韧性非编码RNA：PI的皮，Kim，Slack 摘要（30行） 该提案是对阿尔茨海默氏病和相关的RFA-AG-23-010非编码RNA的回应 痴呆症。拟议的研究的总体目标是定义和表征关键的非编码RNA （NCRNA）生物弹性机制的调节因子对阿尔茨海默氏病（AD）中认知丧失的机制。 一个对与广告相关的神经病理学韧性且不显​​示认知下降的人 与广告相关的神经病理学的存在将不太可能在以后的生活中发展痴呆。一个惊人的自然 在控制或补偿广告相关的同时，旧的子群保持在认知上保持完整 病理。到目前为止，针对特定AD相关病理的药物干预措施，例如β-淀粉样蛋白 神经原纤维缠结或神经炎症，在控制与AD病理学相关的基本上无效 认知能力下降 - 广告相关痴呆症（AD/ADRD）。令人信服的替代方法是找到增强的方法 针对AD/ADRD的弹性。在衰老期间，转录调节过程的保真度随着 功能的相关丧失和认知能力下降。正确编码和非编码基因表达调节是 维持体内稳态和预防疾病过程至关重要。 NCRNA越来越被认可 作为潜在的，在所有级别上的基因表达的高度特异性调节剂。 NCRNA在细胞应力中起关键作用 回复。考虑到大量miRNA和lncRNA基因以及基因/lncRNA/miRNA相互作用以及 这些RNA在细胞正常过程中的总体作用，NCRNA具有巨大的潜力 作为衰老病理学的治疗靶标和生物标志物，也是关键的中间机制 标记 - 有助于定义其调节疾病反应的机制。我们将进行第一个研究 这系统地识别并表征了AD中新型NCRNA调节的弹性机制。衍生的 来自人类主题数据。该项目将建立一个系统的框架来识别弹性 过程，解释了NCRNA在细胞和分子水平上AD的弹性中的作用。我们的 全面的方法将揭示NCRNA对认知能力下降的韧性因素的作用。使用 对认知弹性人群和强大工具的系统分析，这些工具识别有弹性的LNCRNA和 miRNA，我们将识别并表征优先复原力的相互作用，功能和目标 - 在我们的体外神经/神经胶质细胞培养模型和晚期三维（3D）中相关的NCRNA AD的人类神经细胞培养模型。团队汇集了广泛而深厚的跨学科专业知识 在NCRNA生物学，系统生物学和阿尔茨海默氏病病理学中，具有固体基础和转化 科学背景是解决对衰老（Slack），NCRNA靶向（vlachos）的理解的理解， 3D AD模型系统（KIM）和AD（Tanzi）中复杂疾病（隐藏）和专业知识的系统生物学。