Cell-free DNA as a marker of progression in Alzheimer's dementia and its role in chronic inflammation

游离DNA作为阿尔茨海默氏痴呆进展的标志物及其在慢性炎症中的作用

• 批准号: 10725214
• 负责人: Lolita S Nidadavolu
• 金额: $ 32.47万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10725214
• 关键词: Activities of Daily Living; Adult; Affect; Age; Aging; Alzheimer' s Disease; Apoptosis; Biological; Blood; Cell Death; Cell Death Process; Cell Line; Cells; Chicago; Chronic; Clinical; Cognition; Cognitive; Consensus; Development; Diagnosis; Disease; Disease Marker; Disease Progression; Epidemiology; Exposure to; Flow Cytometry; Future; Goals; Human; Immune signaling; Immune system; Impaired cognition; Impairment; Individual; Inflammation; Inflammatory; Innate Immune System; Interferon Type II; Interleukin-1 beta; Interleukin-6; Intervention; Lentivirus; Life; Measures; Mediator; Memory; Memory impairment; Mentored Patient-Oriented Research Career Development Award; Methods; Microglia; Natural Immunity; Necrosis; Neurons; Nuclear; Pathway interactions; Patient Care; Patients; Production; Proteins; Reporter; Role; Sampling; Serum; Signal Pathway; Signal Transduction; Site Visit; Stream; Testing; Training; Universities; Work; burden of illness; cell free DNA; cell type; cognitive testing; cohort; cytokine; digital; high risk; induced pluripotent stem cell; inflammatory marker; innovation; mild cognitive impairment; neuroblastoma cell; neuron loss; novel; progression marker; progression risk; religious order study; response; risk stratification; stable cell line; transcription factor

PROJECT ABSTRACT/SUMMARY: Mild cognitive impairment (MCI) is defined as having impaired cognition in one or more domains with minimal limitations to daily life activities and may represent a timepoint at which interventions for Alzheimer’s disease (AD) can be implemented. However, there is significant variability in rates of progression from MCI to AD; therefore, it is critical to non-invasively identify individuals at highest risk of disease progression. One proposed marker of disease progression is cell-free DNA (cf-DNA), which is released from cell death processes. Measuring serum cf-DNA conveys information about cell death mechanisms that can help us better understand energy changes in the dying cells. Determining the connections between cf-DNA and immune system activation allows us to better recognize factors that contribute to chronic inflammation in MCI and AD. This study hypothesizes that increased cf-DNA levels in individuals with MCI are associated with faster rates of progression to AD, and that cf-DNA contributes to AD-associated chronic inflammation via activation of the nuclear factor kappa-B (NF- kB) pathway. Digital PCR will be used to measure cf-DNA levels in serum of individuals with MCI and normal cognition and associations with rates of cognitive decline will be studied (Aim 1). Differentiated human neuronal cell lines treated with purified cf-DNA from individuals with MCI and normal cognition will be evaluated for changes in inflammatory cytokine production, activation of NF-kB signaling, and cell death (Aim 2). This innovative study has the potential to identify important immune signaling pathways to examine further in the context of AD and can directly impact patient care by utilizing cf-DNA as a marker associated with rates of disease progression in individuals with MCI.

项目摘要/摘要： 轻度认知障碍（MCI）被定义为在一个或多个领域存在认知障碍，且认知障碍程度极低。 日常生活活动受到限制，可能代表阿尔茨海默病干预措施的一个时间点 (AD) 可以实施，但是从 MCI 进展为 AD 的速度存在显着差异； 因此，非侵入性地识别疾病进展风险最高的个体至关重要。 疾病进展的标志物是细胞死亡过程中释放的游离 DNA (cf-DNA)。 血清 cf-DNA 传达有关细胞死亡机制的信息，可以帮助我们更好地了解能量 确定死亡细胞中 cf-DNA 和免疫系统激活之间的联系。 我们可以更好地认识导致 MCI 和 AD 慢性炎症的因素。 MCI 患者 cf-DNA 水平升高与 AD 进展速度加快有关，并且 cf-DNA 通过激活核因子 kappa-B (NF- kB) 途径将用于测量 MCI 和正常个体血清中的 cf-DNA 水平。 将研究认知及其与认知下降率的关联（目标 1）。 将评估用来自 MCI 和正常认知个体的纯化 cf-DNA 处理的细胞系 炎症细胞因子产生、NF-kB 信号传导激活和细胞死亡的变化（目标 2）。 创新研究有可能确定重要的免疫信号通路，以进一步研究 AD 的背景，并且可以通过利用 cf-DNA 作为与 AD 发生率相关的标记物来直接影响患者护理 MCI 个体的疾病进展。