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（R 01 AG 073260 -02;项目于2026年5月31日结束） 母体R 01专注于研究胶质脂滴对氧化应激的影响， 阿尔茨海默病（AD）的神经变性。它需要跨学科的方法来进一步探讨 与年龄相关的ROS与血脂失调、AD危险因素、Aβ42蓄积和 在神经胶质脂滴形成的背景下的Tau。 由于AD是一种与年龄相关的疾病，因此可能有许多与年龄相关的特征影响疾病 发病和进展，包括脂质失调和ROS的异常上调。母 格兰特专注于这些特征如何影响神经元-神经胶质相互作用和AD相关的病理， Aβ42和Tau，在神经系统中。然而，脂质和ROS的失调可能会影响 多种组织值得注意的是，脂质和ROS失调与许多年龄相关， 影响外周的相关疾病，包括心血管疾病、肥胖症和肠 发育不良与此相适应的是，人们越来越有兴趣了解AD与外围国家之间的相互作用 in the context背景of aging老化.因此，AD与肠道微生物组、呼吸系统和免疫系统的破坏有关。 支持外周组织系统、心血管功能和激素稳态也 与疾病有关。然而，AD进展和外周血淋巴细胞增殖之间的因果关系， 失调还没有很好地建立。在这里，我们建议系统地研究AD如何 使用果蝇和细胞图谱在细胞分辨率下，进展影响整个生物体 approach.单细胞RNA测序（scRNA-seq）技术的最新进展和 Fly Cell Atlas（FCA）的建立（图1A）为探索这一点提供了前所未有的机会 细胞层面的潜在关系。FCA是单核转录组数据集，其中 在整个成蝇中鉴定出超过250种细胞类型。通过将snRNA-seq与脂质组学相结合， 目的是强调外周内受毒性Aβ42或Tau影响的细胞机制， 衰老的过程果蝇是一个理想的模型系统，因为这种简单的生物， 快速的寿命和执行相同或相似功能的基因的冗余较少。这 工作目标是表征AD进展如何影响整个生物体中的不同细胞类型 并确定与年龄相关的脂质失调的相互作用。根据标准， 行政补充，我们认为我们的建议非常符合标准， 新技术的可用性（Li等人，2022年）。此外，这种补充是一种自然的延伸， 我们资助的关于非细胞自主机制和脂质失调的研究， 到AD。 1