No NP-positive cells were detected in mock-treated MDCK cells

othesis is true, the probability of observing a pair of p-values whose product, ci = PNDE PPERT is at least as low as that observed for a given pathway Pi is PG ci ci lnci When several tens of subpathways are tested simultaneously, small PG values can occur by chance. Therefore, we control the FDR of the subpathway 1% by applying the commonly used FDR algorithm. ~~ Lipid metabolism is essential for maintaining the structure and function of the visual system. Evidence has shown that chronic misregulation of retinal lipid metabolism can result in retinal degeneration and blindness. Importantly, specific mutations of lipid metabolizing proteins have also been linked to retinal degeneration. These examples include mutations in hepatic lipase gene, the GW 501516 chemical information ATP-binding cassette transporters 1, and lysophosphatidylcholine acyltransferase 1 which all lead to the retinal degeneration. Conversely, lipids also play important prosurvival roles in the retina. Docosahexaenoic acid has been shown to protect photoreceptors and retinal pigment epithelium cells from oxidative damage, and the bioactive lipid product inositol-1, 4, 5-trisphosphate is an important signaling molecule involved in retinal neuroprotection. While these studies have extended our knowledge regarding the roles of lipids in visual function and pathology, many gaps still remain. Sphingolipids represent a major class of lipids that form important components of cellular membranes, and many studies have shown that SPL play important roles in regulating diverse cellular events, such as cell growth arrest, senescence, apoptosis, and inflammation and degeneration. Additionally, studies have provided evidence that misregulation of SPL metabolism can lead to retinal degeneration. Importantly, some lipid PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19748543 storage diseases, which are caused by disorders of sphingolipid metabolism, such as Krabbe’s disease, and Sandhoff disease, are characterized by vision loss. Although current evidence suggests a strong connection between SPL metabolism and retinopathy, the exact roles of these lipids in the retina are mostly unknown. Among various SPL regulating enzymes, acid sphingomyelinase plays an essential role in regulating SPL metabolism by hydrolyzing the phosphodiester bond of sphingomyelin, yielding ceramide, the “hub” of SPL metabolism. Mutations of ASMase result in Niemann-Pick disease types A and B, a fatal autosomal recessive lysosomal storage disorder, presenting both visceral and neurological symptoms. ASMase knockout mice have been generated, providing the animal model for NPD types A and B diseases. In the ASMase KO mice, neuronal degeneration has been identified in the brain, leading to the dysfunction of neuromotor coordination. Progressive degeneration of specific neuronal cell types, specifically cerebellar Purkinje cells, was also identified. However, the molecular mechanism of neurodegeneration in NPD patients is still obscure and the impact on other organ systems has been barely investigated. In the eye, previous studies have provided only limited and conflicting information regarding the impact of ASMase dysregulation on retinal structure and function. As a result the current study was conducted to begin to understand the relationship between sphingolipid metabolism and visual impairments. Morphometric and electroretinogram responses and analysis were PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19748480 used to assess age-dependent changes in retinal structure and function in ASMase KO mice. Our results demonstrate that ASMase is necessary