Equipment Supplement: Regulation of lipid homeostasis by proliferative signaling pathways

项目总结 细胞通过检测细胞外信号来对环境做出反应，这些信号决定了能源资源、 包括脂类，都被利用了。在复杂的组织中，具有特殊新陈代谢功能的细胞 发育、营养和环境投入，严格控制脂质在不同环境中的分配 代谢途径，以维持机体能量的动态平衡。这些通路的失调 会导致代谢性疾病和癌症。控制脂质动态平衡的分子机制， 包括控制代谢流量的细胞间信号和细胞内调节因子，仍然存在 人们对此知之甚少。 增殖信号转导通路，包括mTOR和MAP激酶，促进细胞生长和 影响代谢功能；然而，这些途径的上游调节因子和下游效应因子 控制脂质动态平衡的机制在很大程度上仍不清楚。这项研究计划的长期范围是 发现促生长信号转导通路的新调控因子并阐明其分子 它们发挥代谢控制作用的机制。我们将采用跨学科的方法，使用 无偏遗传策略与功能基因组学和生化分析相结合 生物系统，以解决脂类动态平衡领域的几个基本问题。 虽然已知mTOR和MAP激酶广泛参与代谢和生长控制， 我们对这些途径如何影响脂质分配的理解存在重大差距。这其中的第一个目标是 项目是确定调节mTOR复合体2(MTORC2)活性的组织间信号事件， 这在任何系统中都是鲜为人知的，为了进一步定义mTORC2在 特殊的细胞类型--线虫的肠道。利用无偏见的遗传和基因组的力量 方法，然后我们将确定mTORC2信号的转录效应子，这些转录效应子是 负责控制代谢基因的表达，以便全面了解 MTORC2调节能量动态平衡。 在应激反应和细胞增殖中广泛发挥作用的MAP激酶对维持 细胞内稳态；然而，MAPK信号如何控制脂质代谢途径还知之甚少。 该项目的第二个目标是确定不同的MAPK通路如何影响脂质稳态，然后 研究MAPK和其他促进生长的途径之间的相互作用的潜在途径，最后 采用无偏见的遗传方法确定控制脂质的MAPK信号的下游效应者 动态平衡和生长。总之，这项研究将阐明增殖信号通路是如何起作用的 共同塑造特化细胞的代谢功能，并提供对如何 这些途径的失调会导致代谢功能障碍和疾病。

PROJECT SUMMARY Cells respond to their environment by detecting extracellular signals that dictate how energy resources, including lipids, are utilized. In complex tissues, cells with specialized metabolic functions perceive developmental, nutritional, and environmental inputs that strictly control the allocation of lipids into different metabolic pathways in order to maintain organismal energy homeostasis. Dysregulation of these pathways can lead to metabolic disease and cancer. The molecular mechanisms that govern lipid homeostasis, including the intercellular signals and the intracellular regulatory factors that control metabolic flux, remain poorly understood. Proliferative signal transduction pathways, including mTOR and MAP Kinase, promote cellular growth and influence metabolic function; however, the upstream regulators and downstream effectors of these pathways that control lipid homeostasis remain largely unknown. The long-term scope of this research program is to uncover new regulatory factors of pro-growth signal transduction pathways and to elucidate the molecular mechanisms by which they exert metabolic control. We will employ an interdisciplinary approach, using unbiased genetic strategies in combination with functional genomics and biochemical analyses in different biological systems, to address several fundamental questions in the field of lipid homeostasis. Although mTOR and MAP Kinases are known to participate extensively in metabolic and growth control, major gaps exist in our understanding of how these pathways influence lipid allocation. The first goal of this project is to identify the inter-tissue signaling events that regulate the activity of mTOR Complex 2 (mTORC2), which is poorly understood in any system, and to further define the metabolic function of mTORC2 in a specialized cell type - the C. elegans intestine. Leveraging the power of unbiased genetic and genomic approaches in the worm, we will then identify the transcriptional effectors of mTORC2 signaling that are responsible for controlling the expression of metabolic genes in order to gain a comprehensive view of how mTORC2 regulates energy homeostasis. MAP Kinases, which function broadly in stress responses and cell proliferation, are crucial for maintaining cellular homeostasis; however, how MAPK signaling controls lipid metabolism pathways is poorly understood. The second goal of this project is to define how different MAPK pathways influence lipid homeostasis, then investigate the potential avenues of cross-talk between MAPK and other pro-growth pathways, and finally to employ an unbiased genetic approach to identify the downstream effectors of MAPK signaling that control lipid homeostasis and growth. Together, this research will shed light on how proliferative signaling pathways act together to shape the metabolic function of specialized cells and provide mechanistic insight into how dysregulation of these pathways can lead to metabolic dysfunction and disease.