A NOVEL MECHANISM OF REGULATION OF INOSITOL BIOSYNTHESIS IN YEAST

酵母肌醇生物合成调控的新机制

• 批准号: 7992535
• 负责人: Miriam L Greenberg
• 金额: $ 10万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7992535
• 关键词: ATP phosphohydrolase; Address; Affect; Anabolism; Bipolar Disorder; Calcium; Cell Line; Cells; Complement; Complex; Culture Media; Cytoskeleton; Defect; Diabetes Mellitus; Disease; Drug usage; Enzymes; Epilepsy; Gene Expression; Genes; Genetic Screening; Genetic Transcription; Glycolysis; Goals; Growth; Health; Homeostasis; Human; Inositol; Inositol Phosphates; Lead; Link; Lithium; Malignant Neoplasms; Mediating; Membrane Potentials; Membrane Protein Traffic; Messenger RNA; Metabolic; Molecular; Morphology; Myopathy; Neurologic; Neurons; Organelles; Outcome Study; Pathway interactions; Pharmaceutical Preparations; Phosphatidylinositols; Phospholipid Metabolism; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphorylation Site; Phosphotransferases; Physiological; Play; Proteins; Protons; Pump; Regulation; Regulatory Pathway; Role; Secretory Vesicles; Signal Pathway; Signal Transduction; Signaling Molecule; Site; Sorting - Cell Movement; Synaptic Vesicles; Time; Vacuole; Yeast Model System; Yeasts; base; innovation; inositol 3-phosphate; mutant; neurotransmission; neurotransmitter uptake; novel; public health relevance; sensor; vacuolar H+-ATPase; valproate

DESCRIPTION (provided by applicant): Inositol is an essential metabolite that plays a fundamental role in regulating cellular signaling pathways. In yeast, inositol affects the transcription of over 700 genes. In addition, many inositol phosphates and phosphoinositides are signaling molecules that control essential cellular pathways. Therefore, inositol homeostasis must be highly regulated. Numerous studies have shown that inositol biosynthesis is controlled at the level of transcription of the INO1 gene, which encodes myo-inositol 3-phosphate synthase (MIPS). However, regulation of inositol levels cannot be explained solely by modulating INO1 expression, as several physiological conditions that lead to inositol depletion are characterized by decreased inositol synthesis in spite of an increase in INO1 expression. In fact, preliminary studies indicate that decreased MIPS activity results from phosphorylation of the MIPS protein, not from decreased INO1 mRNA. Interestingly, inhibition of inositol synthesis perturbs vacuole function and V-ATPase activity. Based on these findings, the proposed study will address the hypothesis that inositol homeostasis is controlled by the phosphorylation of MIPS, and that inositol depletion leads to perturbation of vacuolar function and ATPase activity. The V-ATPase is a highly conserved pump that is essential for the transport of molecules into acidic organelles. In synaptic vesicles, V-ATPase activity drives the uptake of neurotransmitters. Therefore, perturbation of the V-ATPase by inositol depleting drugs is expected to have important implications for neurotransmission. The specific aims will address the following questions: 1) What is the mechanism underlying the phosphorylation of MIPS? 2) How does inositol depletion lead to perturbation of vacuolar function? 3) What mechanisms control MIPS in human cells? This study will characterize for the first time a novel regulatory mechanism that controls inositol homeostasis and that links this regulation to vacuolar function and V-ATPase activity. This study will also address the serious gap in our understanding of how inositol synthesis is regulated in human cells. Because inositol-containing compounds are involved in disorders as diverse as neurological and psychiatric illnesses, myopathies, cancer, and diabetes, the outcome of these studies will have a powerful impact on understanding regulatory pathways crucial to human health. PUBLIC HEALTH RELEVANCE: The proposed study will elucidate a novel molecular mechanism of control of inositol homeostasis and the cellular consequences of this regulation. Inositol is an essential metabolic sensor that plays a fundamental role in regulating cellular signaling pathways. Because inositol-containing compounds are involved in disorders as diverse as neurological and psychiatric illnesses, myopathies, cancer, and diabetes, the outcome of these studies will have a powerful impact on understanding regulatory pathways crucial to human health.

描述（由申请人提供）：肌醇是一种重要的代谢物，在调节细胞信号传导途径中发挥重要作用。在酵母中，肌醇影响 700 多个基因的转录。此外，许多磷酸肌醇和磷酸肌醇是控制重要细胞途径的信号分子。因此，肌醇稳态必须受到高度调节。大量研究表明，肌醇生物合成受 INO1 基因转录水平的控制，该基因编码肌醇 3-磷酸合酶 (MIPS)。然而，肌醇水平的调节不能仅仅通过调节 INO1 表达来解释，因为导致肌醇消耗的几种生理条件的特征是尽管 INO1 表达增加，但肌醇合成减少。事实上，初步研究表明，MIPS 活性降低是由于 MIPS 蛋白磷酸化所致，而不是 INO1 mRNA 降低所致。有趣的是，抑制肌醇合成会扰乱液泡功能和 V-ATP 酶活性。基于这些发现，拟议的研究将提出这样的假设：肌醇稳态是由 MIPS 磷酸化控制的，并且肌醇消耗会导致液泡功能和 ATP 酶活性的扰动。 V-ATP 酶是一种高度保守的泵，对于将分子转运到酸性细胞器中至关重要。在突触小泡中，V-ATP 酶活性驱动神经递质的摄取。因此，肌醇消耗药物对 V-ATP 酶的干扰预计会对神经传递产生重要影响。具体目标将解决以下问题：1）MIPS 磷酸化的机制是什么？ 2）肌醇消耗如何导致液泡功能扰动？ 3）什么机制控制人体细胞中的MIPS？这项研究将首次描述一种控制肌醇稳态并将这种调节与液泡功能和 V-ATP 酶活性联系起来的新型调节机制。这项研究还将解决我们对人体细胞中肌醇合成如何调节的理解中的严重差距。由于含肌醇化合物与神经和精神疾病、肌病、癌症和糖尿病等多种疾病有关，因此这些研究的结果将对理解对人类健康至关重要的调节途径产生巨大影响。公共健康相关性：拟议的研究将阐明控制肌醇稳态的新分子机制以及这种调节的细胞后果。肌醇是一种重要的代谢传感器，在调节细胞信号通路中发挥着重要作用。由于含肌醇化合物与神经和精神疾病、肌病、癌症和糖尿病等多种疾病有关，因此这些研究的结果将对理解对人类健康至关重要的调节途径产生巨大影响。