Genetic Regulation of Phospholipid Synthesis in Yeast

描述(由申请人提供)：项目摘要：真核细胞与正在进行的膜生物发生协调控制膜脂合成的机制尚不清楚。然而，磷脂，特别是含有肌醇的磷脂，已经参与了复杂的信号过程，在高等真核生物中发挥着控制细胞生长和增殖的作用。酵母细胞使用与高等真核生物相似的途径合成典型的真核磷脂混合物。这种有机体可以利用强大的分子遗传学进行操纵，并使用新的全基因组技术进行分析。拟议的分析将产生影响磷脂代谢的多个信号通路的相对输入和相互作用的详细模型，磷脂代谢是一个基本的细胞过程，其本身产生的信号反馈产生自我调节循环，并影响其他代谢、膜运输和信号转导途径。将对影响酵母中磷脂代谢的细胞过程的组合输入和相互作用进行遗传评估，包括膜运输、沉默和信号传递。可以在一次实验中定量测定100种或更多代谢物的方法将被用于评估选定突变体及其抑制子的脂代谢，以确定影响这一调节的代谢信号。微阵列分析将被用来探索全基因组范围内基因表达的动力学，以响应脂肪代谢的变化。相关性：了解脂代谢的调节对于应对肥胖、糖尿病和动脉粥样硬化等慢性疾病至关重要。酵母是此类研究的优秀模型系统，因为相关途径对酵母和哺乳动物是共同的，主要酶是同源的，确保从酵母获得的见解将产生与人类健康相关的知识。

DESCRIPTION (provided by applicant): Project Summary: The mechanisms by which eukaryotic cells control the synthesis of membrane lipids in coordination with ongoing membrane biogenesis are not well understood. Yet phospholipids, particularly inositol-containing phospholipids, have been implicated in complex signaling processes which play a role in controlling cell growth and proliferation in higher eukaryotes. Yeast cells synthesize a typically eukaryotic mixture of phospholipids, using pathways which are similar to those in higher eukaryotes. This organism can be manipulated using powerful molecular genetics and analyzed using new genome-wide techniques. The proposed analysis will produce a detailed model of the relative inputs and interactions of multiple signaling pathways influencing phospholipid metabolism, an essential cellular process which itself produces signals that feedback to produce autoregulatory loops and influence other metabolism, membrane trafficking and signal transduction pathways. A genetic assessment will be conducted of the combinatorial inputs and interactions of cellular processes influencing, and influenced by, phospholipid metabolism in yeast including, membrane trafficking, silencing and signaling. Methods which allow quantitative determination of 100 or more metabolites in a single experiment will be used to assess lipid metabolism in selected mutants and their suppressors in order to identify metabolic signals influencing this regulation. Microarray analysis will be used to explore the kinetics of gene expression, genome wide, in response to changes in lipid metabolism. Relevance: An understanding of the regulation of lipid metabolism is critical in dealing with chronic conditions such as obesity, diabetes, and atherosclerosis. Yeast is an excellent model system for such studies since the relevant pathways are common to yeast and mammals and the major enzymes are homologous, ensuring that insights derived from yeast will generate knowledge relevant to human health.