Identification of Genes that Regulate Cellular Lipid Storage

调节细胞脂质储存的基因的鉴定

基本信息

批准号：
7407977
负责人：
ROBERT V FARESE
金额：
$ 28.22万
依托单位：
J. DAVID GLADSTONE INSTITUTES
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-20 至 2009-03-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Cells from nearly all eukaryotic organisms store neutral lipids in cytosolic organelles called lipid droplets or adiposomes. This process is of fundamental importance for cellular energy metabolism, membrane synthesis, and preventing toxicity from an excess of unesterified lipids, such as cholesterol or fatty acids. However, the excessive accumulation of neutral lipids, such as cholesterol esters or triacylglycerols, in tissues is a central feature of the most prevalent metabolic diseases that affect world health, including atherosclerosis, obesity, and type 2 diabetes. Despite the importance of this fundamental aspect of biology, surprisingly little is known about the most basic mechanisms of the cellular synthesis and storage of neutral lipids in cells. The overall goal of this project is to identify the cellular machinery responsible for the synthesis and storage of neutral lipids in adiposomes. We hypothesize that adiposome biosynthesis requires specific genes and that multiple genes regulate adiposome homeostasis. Our goal is to identify these genes and elucidate their functions. Two interrelated aims are proposed that attack the problem, using non-biased, genome-wide screens in cells of different model organisms. Aim 1 is to identify proteins that regulate the number and size of adiposomes using a genome-wide RNAi screen in Drosophila melanogaster S2 cells. Aim 2 is to identify proteins involved in adiposome biogenesis through a mutagenesis based genetic screen in Saccharomyces cerevisiae. The proposed studies have the potential to lead to major new insights that will enhance our understanding both of cell biology and of metabolic diseases characterized by excessive lipid storage. The knowledge gained from these studies could have direct implications for treatment modalities for metabolic syndrome or type 2 diabetes.

描述（由申请人提供）：来自几乎所有真核生物的细胞将中性脂质存储在称为脂质滴或脂质体的胞质细胞器中。这个过程对于细胞能量代谢，膜合成和防止过量的未酯化脂质（例如胆固醇或脂肪酸）的毒性至关重要。然而，组织中中性脂质的过度积累，例如胆固醇酯或三酰基甘油，是影响世界健康的最普遍的代谢性疾病的核心特征，包括动脉粥样硬化，肥胖和2型糖尿病。尽管生物学的这一基本方面很重要，但令人惊讶的是，对细胞合成和中性脂质在细胞中的最基本机制的了解鲜为人知。该项目的总体目标是确定负责脂质体中中性脂质的合成和存储的细胞机械。我们假设脂质体生物合成需要特定的基因，并且多个基因调节脂质体稳态。我们的目标是识别这些基因并阐明其功能。提出了两个相互关联的目的，该目标是使用不同模型生物细胞中的无偏见的全基因组筛选来攻击问题的。目标1是鉴定使用果蝇中果蝇S2细胞中全基因组RNAi筛选来调节脂肪体数量和大小的蛋白质。目的2是通过基于诱变的酿酒酵母中的基于诱变的遗传筛选来鉴定参与脂质体生物发生的蛋白质。拟议的研究有可能导致主要的新见解，从而增强我们对细胞生物学和以脂质储存过多为特征的代谢疾病的理解。从这些研究中获得的知识可能会直接对代谢综合征或2型糖尿病的治疗方式产生影响。