Effects of sphingolipids on nutrient transporter expression and bioenergetics

鞘脂对营养转运蛋白表达和生物能学的影响

• 批准号: 8317814
• 负责人: Aimee L Edinger
• 金额: $ 0.86万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8317814
• 关键词: Affect; Aging; Amino Acids; Animal Model; Apoptosis; Area; Autophagocytosis; Bioenergetics; Calcineurin; Carrier Proteins; Cell Cycle Arrest; Cell Death; Cell physiology; Cells; Cellular biology; Ceramides; Cessation of life; Coupling; Data; Disease; Dose; Down-Regulation; Employee Strikes; Endocytosis; Generations; Glucose Transporter; Investigation; Lead; Link; Lysosomes; MAP Kinase Gene; Mammalian Cell; Mass Spectrum Analysis; Measures; Mediator of activation protein; Medical; Metabolic; Metabolism; Modeling; Molecular; Necrosis; Nerve Degeneration; Non-Insulin-Dependent Diabetes Mellitus; Normal Cell; Nutrient; Pancreas; Pathogenesis; Pathway interactions; Phosphatidylinositols; Phosphoric Monoester Hydrolases; Phosphorylation; Play; Protein Phosphatase 2A Regulatory Subunit PR53; Protein-Serine-Threonine Kinases; Proteins; Publishing; Recycling; Resistance; Role; Secondary to; Signal Transduction; Sphingolipids; Starvation; Stress; Testing; Therapeutic; Toxic effect; Vacuole; Yeasts; analog; cancer cell; cancer type; cell growth; cell killing; chemical genetics; extracellular; falls; human FRAP1 protein; human disease; insight; meetings; methyl pyruvate; neoplastic; new therapeutic target; novel; novel therapeutic intervention; permease; public health relevance; response; scaffold; senescence; stem; trafficking; tumor

DESCRIPTION (provided by applicant): The sphingolipid ceramide promotes cell cycle arrest, differentiation, senescence, and death. The mechanisms by which it affects these cellular processes are poorly defined. My lab has recently published data supporting a new model for ceramide action: starving cells to death. We found that ceramide generation results in rapid and profound nutrient transporter down-regulation in mammalian cells similar to what has been observed in yeast. To respond to this intracellular nutrient limitation, ceramide-exposed cells engage in protective autophagy, a starvation response by which cells digest their constituent molecules to obtain energy and essential nutrients. In further support of this bioenergetic model for ceramide action, supplying cells with a transporter-independent, cell-permeable nutrient, methyl pyruvate, blocked ceramide-induced death. Furthermore, inducing metabolic quiescence by gradually adapting cells to tolerate low extracellular nutrient levels completely eliminated ceramide toxicity. We propose to extend these studies through the following Specific Aims: 1) Identify the molecular pathways between ceramide and nutrient transporter proteins. The mechanisms by which ceramide causes nutrient transporter loss are undefined. We will determine the trafficking step affected by ceramide and whether several established ceramide effector proteins contribute to transporter loss. 2) Determine the mechanism of action for the anti-neoplastic dose of the sphingolipid analog, FTY720. We will determine whether FTY720 kills cells by down-regulating nutrient transporter proteins. We will also test our hypothesis that FTY720 has secondary effects on endocytic trafficking that increase its toxicity. These studies will allow us to refine our bioenergetic model for ceramide action and increase our understanding of how endocytic traffic is regulated. Studies with FTY720 may also serve as proof of the principle that targeting nutrient transporter proteins is a safe and effective therapeutic approach. Ceramide- induced nutrient transporter down-regulation may play an important role in the pathogenesis of cancer and type 2 diabetes. If so, these studies may also identify novel chemotherapeutic targets to treat these prevalent human diseases. PUBLIC HEALTH RELEVANCE: The proposed studies are of broad medical relevance as ceramide plays a key role in many human diseases as well as in aging. The planned studies have particular relevance to cancer and type 2 diabetes and may lead to new therapeutic approaches to these prevalent diseases.

描述（由申请人提供）：鞘脂神经酰胺促进细胞周期阻滞、分化、衰老和死亡。它影响这些细胞过程的机制尚不清楚。我的实验室最近发表的数据支持神经酰胺作用的新模型：将细胞饿死。我们发现神经酰胺的产生导致哺乳动物细胞中营养转运蛋白的快速而深刻的下调，这与在酵母中观察到的相似。为了应对这种细胞内营养限制，神经酰胺暴露的细胞会进行保护性自噬，这是一种饥饿反应，细胞通过消化其组成分子来获得能量和必需的营养。为了进一步支持神经酰胺作用的生物能量模型，向细胞提供一种不依赖于转运蛋白、细胞可渗透的营养物质丙酮酸甲酯，可以阻断神经酰胺诱导的死亡。此外，通过逐渐使细胞适应低细胞外营养水平来诱导代谢静止，完全消除了神经酰胺毒性。我们建议通过以下具体目标来扩展这些研究：1)确定神经酰胺和营养转运蛋白之间的分子途径。神经酰胺导致营养转运体损失的机制尚不明确。我们将确定受神经酰胺影响的运输步骤，以及几种已建立的神经酰胺效应蛋白是否有助于转运蛋白的损失。2)确定鞘脂类似物FTY720抗肿瘤剂量的作用机制。我们将确定FTY720是否通过下调营养转运蛋白杀死细胞。我们还将测试我们的假设，即FTY720对内吞贩运具有次要影响，从而增加其毒性。这些研究将使我们能够完善神经酰胺作用的生物能量模型，并增加我们对内吞交通如何调节的理解。FTY720的研究也可以证明靶向营养转运蛋白是一种安全有效的治疗方法。神经酰胺诱导的营养转运蛋白下调可能在癌症和2型糖尿病的发病机制中起重要作用。如果是这样，这些研究也可能确定新的化疗靶点来治疗这些流行的人类疾病。