Lipid mediated regulation of stem cell behavior and tissue homeostasis

脂质介导的干细胞行为和组织稳态调节

• 批准号: 10524394
• 负责人: DANA LEANNE JONES
• 金额: $ 38.1万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10524394
• 关键词: Lipid; mediated; regulation; stem; cell

Project Summary Tissue stem cells provide for the maintenance and regeneration of organs and tissues throughout life. The ability of stem cells to contribute to tissue homeostasis depends on their unique ability to generate new stem cells (self-renewal), as well as specialized cell types (differentiation). Stem cell behavior is influenced by the integration of intrinsic factors with extrinsic cues provided by the local microenvironment (or “niche”) and circulating, systemic factors. Thus, identification and characterization of the mechanisms that are involved in regulating stem cell behavior holds significant promise for the maintenance, manipulation and expansion of stem cells for use in regenerative medicine. The capacity of stem cells to self-renew or differentiate has been attributed to distinct metabolic states. Our lab recently found that an increase in triacylglycerides (TAG) in the form of lipid droplets (LDs), either through disruption of fatty acid oxidation (FAO) or stimulation of lipid anabolism, correlates with a loss of germline stem cell (GSC) fate in the Drosophila testis. Genetic or pharmacologic enhancement of lipid catabolism rescued the loss of GSCs, indicating that GSCs are sensitive to the levels of intracellular lipids. Here, we propose to identify the mechanism(s) by which ectopic lipid accumulation leads to loss of GSC identity and to use the well- characterized Drosophila male germline as a model to uncover mechanisms used to tightly regulate lipid metabolism in GSCs to maintain tissue homeostasis through the following Specific Aims: Aim 1: To characterize mechanisms by which increased intracellular lipids contribute to loss of GSCs Aim 2: To investigate the role of phosphatidic acid (PA) metabolism in the Drosophila testis Aim 3: To characterize the role of the phosphatidic acid phosphatase (PAP) dLipin in the Drosophila testis Taken together, these Aims will contribute to a better understanding of how lipid metabolism can influence tissue homeostasis by influencing stem cell behavior. Furthermore, our work will provide a genetic model to characterize mechanisms that cells in non-adipose tissues use to manage ectopic lipids to avoid lipotoxicity. Finally, our findings will provide important insights into how stem cell and/or germ cell function may be altered in individuals suffering from metabolic disorders, such as obesity and/or type 2 diabetes, leading to strategies to regulate stem cell function, in vivo, in patients by modulating metabolic pathways pharmacologically or through diet.

项目摘要 组织干细胞在整个生命过程中提供器官和组织的维持和再生。的 干细胞促进组织稳态的能力取决于它们产生新干细胞的独特能力。 细胞（自我更新），以及专门的细胞类型（分化）。干细胞的行为受到 内在因素与当地微环境（或“生态位”）提供的外在线索的整合， 循环系统因素因此，识别和表征参与的机制， 调节干细胞的行为对干细胞的维持、操作和扩增具有重要意义。 用于再生医学的细胞。 干细胞自我更新或分化的能力归因于不同的代谢状态。我们 一个实验室最近发现，增加甘油三酯（TAG）的形式脂滴（LD），无论是通过 脂肪酸氧化（FAO）的破坏或脂质抑制剂的刺激，与种系干细胞的损失相关 细胞（GSC）在果蝇睾丸中的命运。遗传或药理学增强脂质catalysts挽救了 GSC的损失，表明GSC对细胞内脂质的水平敏感。在这里，我们建议确定 异位脂质积聚导致GSC身份丧失的机制，以及使用良好的- 以果蝇雄性生殖系为模型，揭示了用于严格调节脂质的机制， 通过以下特定目的，在GSC中调节代谢以维持组织稳态： 目的1：表征细胞内脂质增加导致GSC损失的机制 目的2：探讨磷脂酸（PA）在果蝇睾丸中的代谢作用 目的3：研究磷脂酸磷酸酶（PAP）dLipin在果蝇中的作用 睾丸 总而言之，这些目标将有助于更好地了解脂质代谢如何影响 通过影响干细胞的行为来维持组织的稳态。此外，我们的工作将提供一个遗传模型， 表征非脂肪组织中的细胞用于管理异位脂质以避免脂毒性的机制。 最后，我们的研究结果将为干细胞和/或生殖细胞功能如何改变提供重要的见解， 患有代谢紊乱如肥胖症和/或2型糖尿病的个体，导致了 在体内通过调节代谢途径或通过以下途径调节患者的干细胞功能： 饮食.