Regulation of lipid homeostasis by proliferative signaling pathways

通过增殖信号通路调节脂质稳态

• 批准号: 10629408
• 负责人: Robert Houston Dowen
• 金额: $ 38.15万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629408
• 关键词: Address; Biochemical; Caenorhabditis elegans; Cell Proliferation; Cell physiology; Cells; Complex; Development; Environment; Event; FRAP1 gene; Genes; Genetic Transcription; Genomic approach; Goals; Growth; Homeostasis; Human; Intestines; Lipids; MAP Kinase Gene; Malignant Neoplasms; Metabolic; Metabolic Control; Metabolic Diseases; Metabolic Pathway; Metabolic dysfunction; Mitogen-Activated Protein Kinases; Modeling; Molecular; Nutritional; Pathway interactions; Proteins; Regulation; Research; Resources; Shapes; Signal Pathway; Signal Transduction; Signal Transduction Pathway; System; Tissues; Work; biological adaptation to stress; biological systems; cell growth; cell type; extracellular; functional genomics; genetic approach; insight; interdisciplinary approach; lipid metabolism; programs

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.

项目摘要 细胞通过检测细胞外信号对环境做出反应，这些信号决定了能量资源， 包括脂质。在复杂的组织中，具有特殊代谢功能的细胞 发展，营养和环境投入，严格控制脂质分配到不同的 代谢途径，以维持生物体能量稳态。这些途径的失调 会导致代谢疾病和癌症控制脂质稳态的分子机制， 包括控制代谢流的细胞间信号和细胞内调节因子， 不太了解。 包括mTOR和MAP激酶在内的信号转导通路促进细胞生长， 影响代谢功能;然而，这些途径的上游调节子和下游效应子 控制脂质体内平衡的基因仍然是未知的。这项研究计划的长期范围是 发现促生长信号转导途径的新调控因子，阐明促生长信号转导途径的分子机制， 它们控制新陈代谢的机制。我们将采用跨学科的方法， 无偏遗传策略结合功能基因组学和生物化学分析， 生物系统，以解决脂质稳态领域的几个基本问题。 尽管已知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。第一个目标是 该项目旨在确定调节mTOR复合物2（mTORC 2）活性的组织间信号传导事件， 这在任何系统中都是知之甚少的，为了进一步定义mTORC 2的代谢功能， 专门的细胞类型-C。线虫肠利用无偏见的遗传学和基因组学 在蠕虫的方法，我们将确定mTORC 2信号的转录效应， 负责控制代谢基因的表达，以便全面了解 mTORC 2调节能量稳态。 MAP激酶在应激反应和细胞增殖中广泛发挥作用，对于维持细胞增殖至关重要。 细胞内稳态;然而，MAPK信号传导如何控制脂质代谢途径知之甚少。 本项目的第二个目标是确定不同的MAPK途径如何影响脂质稳态， 研究MAPK和其他促生长途径之间的潜在交叉途径，最后， 采用无偏遗传方法来鉴定控制脂质的MAPK信号传导的下游效应物， 稳态和生长。总之，这项研究将揭示增殖信号通路如何发挥作用， 共同塑造特化细胞的代谢功能，并提供关于 这些途径的失调可导致代谢功能障碍和疾病。

项目成果

Exploring the evolution and function of Canoe's intrinsically disordered region in linking cell-cell junctions to the cytoskeleton during embryonic morphogenesis.

• DOI: 10.1371/journal.pone.0289224
• 发表时间: 2023
• 期刊: PloS one
• 影响因子: 3.7

The C. elegansflr-3(ut9) mutation is a loss-of-function insertion within the drl-1 locus.

• DOI: 10.17912/micropub.biology.001047
• 发表时间: 2023
• 期刊: microPublication biology
• 作者: Honey, Kendra L;Torzone, Sarah K;Dowen, Robert H
• 通讯作者: Dowen, Robert H

Opposing action of the FLR-2 glycoprotein hormone and DRL-1/FLR-4 MAP kinases balance p38-mediated growth and lipid homeostasis in C. elegans.

• DOI: 10.1371/journal.pbio.3002320
• 发表时间: 2023-09
• 期刊: PLoS biology
• 影响因子: 9.8

Exploring the evolution and function of Canoe’s intrinsically disordered region in linking cell-cell junctions to the cytoskeleton during embryonic morphogenesis.

探索 Canoe 本质上无序区域在胚胎形态发生过程中将细胞-细胞连接与细胞骨架连接起来的进化和功能。

• DOI: 10.1101/2023.03.06.531372
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Gurley,NoahJ;Szymanski,RachelA;Dowen,RobertH;Butcher,TAmber;Ishiyama,Noboru;Peifer,Mark
• 通讯作者: Peifer,Mark