Lipid mediated regulation of stem cell behavior and tissue homeostasis

项目摘要 组织干细胞为整个生命过程中器官和组织的维持和再生提供了条件。这个 干细胞促进组织动态平衡的能力取决于其产生新干细胞的独特能力 细胞(自我更新)以及特殊细胞类型(分化)。干细胞的行为受到 将本地微环境(或“生态位”)提供的内在因素与外在线索相结合 循环系统因素。因此，识别和表征参与其中的机制 调节干细胞的行为对干细胞的维持、操作和扩增具有重要的前景 用于再生医学的细胞。 干细胞自我更新或分化的能力被归因于不同的代谢状态。我们的 实验室最近发现，三酰甘油酯(TAG)以脂滴(LDS)的形式增加，可以通过 脂肪酸氧化(FAO)的中断或脂肪合成代谢的刺激与生殖系茎的丢失相关 果蝇睾丸细胞(GSC)的命运。遗传或药物增强的脂类分解代谢拯救了 GSCs丢失，表明GSCs对细胞内脂质水平敏感。在这里，我们建议确定 异位脂质堆积导致GSC特性丧失的机制(S) 以果蝇雄性生殖系为模型揭示严密调节血脂的机制 GSCs中的新陈代谢通过以下特定目标维持组织内环境平衡： 目的1：研究细胞内脂质增加导致GSCs丢失的机制 目的2：探讨磷脂酸(PA)代谢在果蝇睾丸中的作用 目的3：研究果蝇磷脂酸性磷酸酶(PAP)dLipin的作用 睾丸 总而言之，这些目标将有助于更好地理解脂肪代谢如何影响 通过影响干细胞的行为实现组织动态平衡。此外，我们的工作将提供一个遗传模型来 描述非脂肪组织中的细胞用来管理异位脂类以避免脂毒性的机制。 最后，我们的发现将为干细胞和/或生殖细胞功能如何改变提供重要的见解。 患有代谢紊乱的个人，如肥胖症和/或2型糖尿病，导致采取战略 在体内，通过药物或通过调节代谢途径来调节患者的干细胞功能 节食。

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.