Regulation of tissue stem cell lineages by nuclear receptor signaling

项目总结 在生物体的一生中，干细胞是组织维持和修复所必需的。改变的生物体 生理学可以通过破坏内分泌组织来影响组织的动态平衡，从而导致脂肪的变化。 细胞代谢、类固醇和激素水平，以及体内循环因子的分泌。秘而不宣 各种因素将遥远器官的生理状态相互传递。核受体(NRs)是 具有配体结合区的广泛表达的转录因子介导循环效应 整个有机体中的各种因素。NRs是能量平衡的主要调节者，包括碳水化合物 代谢、脂肪酸合成和β氧化，并在干细胞分化中发挥重要作用， 新陈代谢和组织动态平衡。然而，NRS用来调节转录的机制 在多种器官和细胞类型中控制远端干细胞谱系以实现适当的组织功能的景观是 未得到充分研究。果蝇卵巢是了解器官间相互作用的理想模型 NR信号介导的通讯影响生殖系干细胞(GSC)谱系。之前的研究已经 表明NRs直接作用于GSCs来调节卵子的发生；然而，有新的证据表明 周围组织中NRS的活性间接影响GSC的谱系。例如，NR七喜(SVP) 脂肪细胞内的作用影响GSC的维持和早期生殖细胞囊性存活和肝细胞样细胞 调节卵黄化卵室存活的细胞。此外，成人肌肉中需要HR4来维持 GSCs和促进卵泡生长。我们研究计划的目标是确定信号如何 不同组织中转录因子的下游影响调节干细胞的循环因子 血统和组织功能。在这项提案中，我们将结合遗传学、细胞生物学和下一步-- 使用NRS和果蝇卵巢作为模型解决两个主要问题的世代测序：1)如何 转录因子是否协调它们在多种组织和细胞类型中的活性，以调节干细胞的行为？ 2)NR如何在器官中保持定向能量稳态，以确保干细胞谱系和 维持组织功能？总体而言，这些项目将为理解 外周组织中转录因子影响成人行为的下游机制 干细胞谱系。此外，这项工作将为未来的研究提供信息，这些研究将集中于了解如何破坏 内分泌信号导致组织和器官衰竭。

PROJECT SUMMARY Stem cells are required for tissue maintenance and repair during the lifetime of an organism. Altered organism physiology can influence tissue homeostasis through disruption of endocrine tissues, resulting in changes in fat cell metabolism, steroid and hormone levels, and secretion of circulating factors within the body. Secreted factors communicate the physiological status of distant organs to one another. Nuclear receptors (NRs) are broadly expressed transcription factors with ligand-binding domains that mediate the effects of circulating factors throughout an organism. NRs are major regulators of energy homeostasis, including carbohydrate metabolism, fatty acid synthesis, and beta oxidation and play important roles in stem cell differentiation, metabolism, and tissue homeostasis. However, the mechanisms used by NRs to modulate the transcriptional landscapes in multiple organs and cell types to control distal stem cell lineages for proper tissue function are understudied. The Drosophila melanogaster ovary is an ideal model to understand how inter-organ communication mediated by NR signaling influences germline stem cell (GSC) lineages. Previous studies have shown that NRs act directly in GSCs to regulate oogenesis; however, there is emerging evidence that the activity of NRs in peripheral tissues indirectly influence the GSC lineage. For example, the NR Seven-Up (Svp) acts within adipocytes to influence GSC maintenance and early germline cyst survival and in hepatocyte-like cells to regulate survival of vitellogenic egg chambers. In addition, Hr4 is required in adult muscle to maintain GSCs and promote follicle growth. The goal of our research program is to determine how signaling downstream of transcription factors in different tissues influences circulating factors that regulate stem cell lineages and tissue function. In this proposal, we will use a combination of genetics, cell biology, and next- generation sequencing to address two major questions using NRs and the Drosophila ovary as models: 1) How do transcription factors coordinate their activity in multiple tissues and cell types to regulate stem cell behavior? 2) How is NR directed energy homeostasis maintained in organs to ensure survival of stem cell lineages and maintain tissue function? Overall, these projects will provide the foundation towards understanding the downstream mechanisms used by transcription factors in peripheral tissues to influence the behavior of adult stem cell lineages. Furthermore, this work will inform future studies focused on understanding how disrupted endocrine signaling results in tissue and organ failure.