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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

基本信息

批准号：
8730169
负责人：
Aimee L Edinger
金额：
$ 27.91万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-30 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8730169
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 response scaffold senescence stem trafficking tumor

项目摘要

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.

描述(申请人提供)：神经鞘脂神经酰胺促进细胞周期停滞、分化、衰老和死亡。它影响这些细胞过程的机制还不是很清楚。我的实验室最近公布了支持神经酰胺作用的新模型的数据：饿死细胞。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快速而深刻的下调，类似于在酵母中观察到的情况。为了应对这种细胞内营养限制，神经酰胺暴露的细胞进行保护性自噬，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要的营养。为了进一步支持神经酰胺作用的生物能量模型，为细胞提供一种非转运体、细胞通透性的营养物质--丙酮酸甲酯，阻断了神经酰胺诱导的死亡。此外，通过逐渐使细胞适应低的细胞外营养水平来诱导代谢停顿，完全消除了神经酰胺的毒性。我们建议通过以下具体目标扩展这些研究：1)确定神经酰胺和营养转运蛋白之间的分子通路。神经酰胺导致营养转运蛋白丢失的机制尚不清楚。我们将确定神经酰胺影响的转运步骤，以及几种已建立的神经酰胺效应蛋白是否导致转运蛋白丢失。2)确定鞘磷脂类似物FTY720的抗肿瘤作用机制。我们将确定FTY720是否通过下调营养转运蛋白来杀死细胞。我们还将检验我们的假设，即FTY720对增加其毒性的内吞转运具有辅助作用。这些研究将使我们能够完善我们的神经酰胺作用的生物能量模型，并增加我们对内吞运输如何调节的理解。FTY720的研究也可以证明，以营养转运蛋白为靶点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。如果是这样的话，这些研究还可能确定新的化疗靶点来治疗这些流行的人类疾病。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Effects of stereochemistry, saturation, and hydrocarbon chain length on the ability of synthetic constrained azacyclic sphingolipids to trigger nutrient transporter down-regulation, vacuolation, and cell death.

立体化学、饱和度和烃链长度对合成受限氮杂环鞘脂触发营养转运蛋白下调、空泡形成和细胞死亡能力的影响。

DOI：
10.1016/j.bmc.2016.07.038
发表时间：
2016
期刊：
Bioorganic & medicinal chemistry
影响因子：
3.5
作者：
Perryman,MichaelS;Tessier,Jérémie;Wiher,Timothy;O'Donoghue,Heather;McCracken,AlisonN;Kim,SeongM;Nguyen,DeanG;Simitian,GrigorS;Viana,Matheus;Rafelski,Susanne;Edinger,AimeeL;Hanessian,Stephen
通讯作者：
Hanessian,Stephen

Branched chain amino acid metabolism and cancer: the importance of keeping things in context.

支链氨基酸代谢和癌症：了解事物背景的重要性。