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对阿尔茨海默病的恢复力：PI的Hide，Kim，Slack 摘要（30行） 该提案是对老年痴呆症和相关疾病中RFA-AG-23-010非编码RNA的回应。 痴呆症这项研究的首要目标是定义和表征关键的非编码RNA （ncRNA）调节剂的生物弹性机制对阿尔茨海默病（AD）中的认知丧失。 对AD相关神经病理学有弹性并且尽管存在AD相关神经病理学， AD相关神经病理学的存在将不太可能在以后的生活中发展为痴呆症。一个惊人的自然 老年人亚群在控制或补偿AD相关的认知功能时保持完整。 病理到目前为止，针对特定AD相关病理的药物干预，如β-淀粉样蛋白， 神经纤维缠结或神经炎症在控制AD病理学相关的 认知功能减退- AD相关痴呆（AD/ADRD）。一个令人信服的替代方案是找到增强 抗AD/ADRD的能力。在衰老过程中，转录调控过程的保真度随着衰老而下降。 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 对于维持体内平衡和预防疾病过程至关重要。ncRNA越来越多地被认识到 作为所有水平的基因表达的有效的、高度特异性的调节剂。ncRNA在细胞应激中起关键作用 反应考虑到大量的miRNA和lncRNA基因以及基因/lncRNA/miRNA相互作用， 由于这些RNA在细胞正常过程中的重要作用，ncRNA不仅具有巨大的潜力， 作为衰老病理学的治疗靶点和生物标志物， 标记物-帮助定义它们调节的疾病反应机制。我们将进行第一项研究 系统地识别和表征AD中新的ncRNA调节的弹性机制; 从人类受试者的数据。该项目将建立一个系统的框架， 过程，以解释在细胞和分子水平的抗AD的ncRNA的作用。我们 全面的方法将揭示ncRNA因子对认知能力下降的恢复力的作用。使用 认知弹性人群的系统分析和识别弹性lncRNA的强大工具， miRNAs，我们将确定和表征优先恢复力的相互作用，功能和目标- 相关的ncRNA在我们的体外神经元/神经胶质细胞培养模型和先进的三维（3D） AD的人类神经细胞培养模型。该团队汇集了广泛而深入的跨学科专业知识 在ncRNA生物学，系统生物学和阿尔茨海默病病理学，具有坚实的基础和翻译 科学背景，以解决衰老中ncRNA的理解（Slack），ncRNA靶向（Vlachos）， 复杂疾病的系统生物学（Hide）和3D AD模型系统（Kim）和AD（Tanzi）的专业知识。