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. ? ? ?
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