IMPACTS OF GLIAL LIPID DROPLETS ON OXIDATIVE STRESS AND NEURODEGENERATION IN ALZHEIMER'S DISEASE

胶质脂滴对阿尔茨海默病氧化应激和神经变性的影响

• 批准号: 10804252
• 负责人: HUGO J BELLEN
• 金额: $ 32.95万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10804252
• 关键词: Administrative Supplement; Adult; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease risk; Amyloid beta-42; Atlases; Award; Biological Models; Cardiovascular Diseases; Cardiovascular Physiology; Cell Nucleus; Cells; Data Set; Disease; Disease Progression; Drosophila genus; Funding; Genes; Homeostasis; Hormones; Intestinal Intraepithelial Neoplasia; Investigation; Lipids; Longevity; Nerve Degeneration; Nervous System; Neurons; Obesity; Onset of illness; Organism; Oxidative Stress; Parents; Pathology; Peripheral; Process; Resolution; Respiratory System; Risk Factors; Technology; Tissues; Up-Regulation; Whole Organism; Work; age related; cell type; fly; gut microbiome; interdisciplinary approach; interest; lipidomics; new technology; parent grant; single nucleus RNA-sequencing; single-cell RNA sequencing; tau Proteins; transcriptomics

Summary – Administrative Supplement Funded Parent Award (R01 AG073260-02; project ends on 05/31/2026) The parent R01 is focused on studying the impacts of glial lipid droplets on oxidative stress and neurodegeneration in Alzheimer's disease (AD). It takes an interdisciplinary approach to further probe connections between age-related ROS and lipid dysregulation, AD risk factors, Aβ42 accumulation and Tau in the context of glial lipid droplet formation. As AD is an age-associated disease, there are likely numerous aging-related features that impact disease onset and progression, including the dysregulation of lipids and aberrant upregulation of ROS. The parent grant focuses on how these features impact neuron-glial interactions and AD-associated pathologies, Aβ42 and Tau, in the nervous system. However, the dysregulation of lipids and ROS is likely to impact multiple tissues. It is notable that lipid and ROS dysregulation is associated with numerous age- associated diseases impacting the periphery, including cardiovascular disease, obesity, and intestinal dysplasia. Fittingly, there is growing interest in understanding the interplay between AD and the periphery in the context of aging. As such, AD has been connected to disruptions in the gut microbiome, respiratory system, cardiovascular function, and hormone homeostasis, supporting that peripheral tissues are also involved in disease. However, a causal relationship between AD progression and peripheral dysregulation is not well established. Here, we propose to systematically investigate how AD progression impacts an entire organism at cellular resolution using Drosophila and a cell atlas approach. Recent advances in single-cell RNA sequencing (scRNA-seq) technologies and the establishment of the Fly Cell Atlas (FCA) (Fig. 1A) offer an unprecedented opportunity to explore this potential relationship at the cellular level. The FCA is a single-nucleus transcriptomic dataset in which over 250 cell types were identified in the whole adult fly. By combining snRNA-seq with lipidomics we aim to highlight cellular mechanisms within the periphery that are impacted by toxic Aβ42 or Tau during the aging process. Drosophila is an ideal model system for such investigations as this simple organism, a rapid lifespan and less redundancies in terms of genes that perform the same or similar functions. This work targets to characterize how AD progression affects different cell types across the whole organism and to define interactions with age-associated lipid dysregulation. Based on the criteria for Administrative Supplements, we believe that our proposal fits very well for the criteria of availability of a new technology (Li et al., 2022). Further, this supplement is a natural extension of our funded studies on non-cell autonomous mechanisms and lipid dysregulation that contribute to AD. 1

摘要 – 行政补充 资助家长奖（R01 AG073260-02；项目于 2026 年 5 月 31 日结束） 母体R01专注于研究胶质脂滴对氧化应激和 阿尔茨海默病（AD）的神经退行性疾病需要跨学科的方法来进一步探讨。 年龄相关的 ROS 与脂质失调、AD 危险因素、Aβ42 积累和 神经胶质脂滴形成背景下的 Tau 蛋白。 由于 AD 是一种与年龄相关的疾病，因此可能有许多与衰老相关的特征会影响疾病 发病和进展，包括脂质失调和 ROS 异常上调。 资助重点关注这些特征如何影响神经胶质细胞相互作用和 AD 相关病理， 然而，神经系统中的 Aβ42 和 Tau，脂质和 ROS 的失调可能会产生影响。 值得注意的是，脂质和活性氧失调与许多年龄相关。 影响周边的相关疾病，包括心血管疾病、肥胖和肠道疾病 人们越来越有兴趣了解 AD 与周围环境之间的相互作用。 因此，AD 与肠道微生物群、呼吸系统的破坏有关。 系统、心血管功能和激素稳态，支持外周组织也 然而，AD 进展与外周疾病之间存在因果关系。 在此，我们建议系统地研究 AD 是如何发生的。 使用果蝇和细胞图谱影响整个生物体的细胞分辨率进展 单细胞 RNA 测序 (scRNA-seq) 技术的最新进展和 Fly Cell Atlas (FCA)（图 1A）的建立为探索这一问题提供了前所未有的机会 FCA 是一个单核转录组数据集，其中 通过将 snRNA-seq 与脂质组学相结合，我们在整个成年果蝇中鉴定出了超过 250 种细胞类型。 旨在强调在过程中受有毒 Aβ42 或 Tau 影响的外周细胞机制 果蝇是研究这种简单生物体的理想模型系统， 执行相同或相似功能的基因寿命短且冗余少。 工作目标是表征 AD 进展如何影响整个生物体的不同细胞类型 并根据年龄相关的脂质失调的标准来定义相互作用。 行政补充，我们相信我们的建议非常符合以下标准： 此外，这种补充是新技术的自然延伸。 我们资助的关于非细胞自主机制和脂质失调的研究有助于 到公元 1