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 资助的家长奖（R01 AG073260-02；项目在2010年5月31日结束） 母体R01专注于研究神经胶质脂质液滴对氧化应激和 阿尔茨海默氏病（AD）中的神经变性。它采用跨学科的方法来进一步探究 与年龄相关的ROS与脂质失调，AD风险因素，Aβ42积累和 在神经胶质脂质液滴形成的背景下。 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 发作和进展，包括脂质的失调和ROS的异常上调。父母 格兰特专注于这些特征如何影响神经胶质相互作用和与广告相关的病理， 神经系统中的Aβ42和tau。但是，脂质和ROS的失调可能会影响 多次。值得注意的是，脂质和ROS功能障碍与许多年龄有关 影响周围的相关疾病，包括心血管疾病，肥胖和肠道 发育不良。合适的是，人们对理解AD与周围之间的相互作用越来越兴趣 在衰老的背景下。因此，AD已与肠道微生物组的破坏有关 系统，心血管功能和骑马稳态，支持周围组织也是 参与疾病。但是，广告进展与周围之间的因果关系 失调尚未确定。在这里，我们建议系统地研究AD 进展使用果蝇和细胞地图集在细胞分辨率下影响整个生物体 方法。单细胞RNA测序（SCRNA-SEQ）技术的最新进展和 建立飞池地图集（FCA）（图1A）为探索这一点提供了前所未有的机会 细胞水平的潜在关系。 FCA是一个单核转录组数据集 在整个成年蝇中发现了250多种细胞类型。通过将snRNA-seq与脂质组学结合在一起 旨在强调周围内受到有毒Aβ42或TAU影响的细胞机制 衰老过程。果蝇是这种简单有机体等投资的理想模型系统， 在执行相同或相似功能的基因方面，寿命快速且冗余不足。这 工作目标以表征AD进展如何影响整个生物的不同细胞类型 并定义与年龄相关脂质失调的相互作用。根据 行政补品，我们认为我们的提案非常适合 新技术的可用性（Li等，2022）。此外，这种补充是自然的扩展 我们关于无促进的非细胞自主机制和脂质失调的资助研究 广告。 1