Genetic Regulation of Phospholipid Synthesis in Yeast

描述（由申请人提供）：真核细胞控制膜脂质合成与持续膜生物发生协调的机制尚未完全了解。 然而，磷脂，特别是含有肌醇的磷脂，已经涉及复杂的信号传导过程，其在控制高等真核生物的细胞生长和增殖中发挥作用。 酵母细胞合成磷脂的典型真核混合物，使用类似于高等真核生物中的途径。 这种生物可以使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。 拟议的分析将产生一个详细的模型的相对输入和相互作用的多个信号通路影响磷脂代谢，一个重要的细胞过程，本身产生的信号，反馈产生自动调节回路和影响其他细胞途径。 将对影响酵母磷脂代谢调节的细胞过程的组合输入和相互作用进行遗传评估，包括膜运输和信号传导。 允许在单个实验中定量测定100种或更多种代谢物的方法将用于评估选定突变体及其抑制子中的脂质代谢，以鉴定影响该调节的代谢信号。 微阵列分析将用于探索基因表达的动力学，基因组范围内，在响应脂质代谢的变化。 这种分析有望阐明真核生物代谢和细胞生物学的基本方面的调控，这些方面与代谢性疾病如糖尿病以及癌症和心脏病有关。

DESCRIPTION (provided by applicant): 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 signalling processess 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 signalling pathways influencing phospholipid metabolism, an essential cellular process which itself produces signals that feedback to produce autoregulatory loops and influence other cellular pathways. A genetic assessment will be conducted of the combinatorial inputs and interactions of cellular processes influencing regulation of phospholipid metabolism in yeast including, membrane trafficking, and signalling. 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. This analysis is expected to shed light on regulation of fundamental aspects of eukaryotic metabolism and cell biology relevant to metabolic diseases such as diabetes, as well as cancer and heart disease.