Seminar: Cholesterol and the Retina: Twists and Turns of Biology and Pathobiology

Fliesler Seminar Flyer

Steven J. Fliesler, UB Distinguished Professor and Chair of Ophthalmology at University of Buffalo/State University of New York (SUNY) will be delivering a seminar on Cholesterol and the Retina: Twists and Turns of Biology and Pathobiology on Thursday, October 8th at 11:30am  in the the Moran Eye Center auditorium.

Abstract: Cholesterol is a ubiquitous component of almost all cellular membranes in higher eukaryotes, and is, by far, the dominant sterol in all mammalian cells and tissues. Excessive levels of blood-borne cholesterol and deposition in extracellular matrices has long been causally associated with cardiovascular disease and age-related diseases, such as Alzheimer’s and age-related macular degeneration. However, a paucity of cholesterol also can be deleterious, even lethal. Hence, defective cholesterol biosynthesis can lead to disruption of cellular and systemic physiology, resulting in profound pathologies. Merely providing exogenous cholesterol does not effectively ameliorate these pathologies. The Fliesler lab has shown that inhibiting the last step in cholesterol synthesis in an animal model, mimicking a human recessive disease known as the Smith-Lemli-Opitz Syndrome (SLOS), causes a progressive and irreversible retinal degeneration. However, the molecular mechanism underlying this degeneration is complex, involving marked lipidomic, proteomic, and genomic changes. Lipid and protein oxidation, as well as oxysterol formation, have been implicated in this retinal degeneration. These findings suggest that blocking such oxidation (with antioxidants) may provide a useful adjunct to cholesterol supplementation (the current standard of care) as a therapeutic intervention for human patients afflicted with diseases involving defective cholesterol biosynthesis, such as SLOS. Preliminary clinical study results support this prediction.

EMT And Myofibroblast Generation In An Injured Lens

Seminar Flyer - Saika

Shizuya Saika, Professor and Chairman of Wakayama Medical University will be delivering a seminar on EMT and myofibroblast generation in an injured lens: modulation of TGFb/Smad signal by extracellular matrix on Tuesday, October 6th at Noon  in the the Moran Eye Center auditorium.

Abstract: EMT and myofibroblast appears in the fibrotic tissues that are undergoing wound healing process. In the eye it is observed in the crystalline lens or other ocular tissues. Transforming growth factor beta (TGFβ)/Smad signal plays a central role in the process of EMT and myofibroblast generation in an injured mouse lens. However, EMT is further modulated by signals derived from binding of extracellular matrix (ECM) to cell surface receptors. In the current talk the mechanisms of modulation of EMT by matricellular proteins, i. e., osteopontin, tenscin-C and lumican through modulation of TGFβ signal. Lacking one of these component suppressed activation of TGFβ signal as revealed by mutant mouse lines. Although overall signals derived from these ECM components support Smad signal and positively modulate EMT, the detailed mechanisms of actions seem differ among each other.

Missense variant in CST3 Exerts Recessive Effect On Susceptibility to AMD

paraoan

There is an interesting paper out demonstrating that CST3 exerts a recessive effect on susceptibility to AMD.  Cystatin C is a potent inhibitor of cysteine proteinases expressed by many tissues and in the eye, it is highly expressed by the retinal pigment epithelium (RPE). The team led by Luminita Paraoan recently reported data identifying a polymorphism in the cystatin C gene (CST3) that increases the risk of two major degenerative diseases, age-related macular degeneration (AMD) and Alzheimer’s disease.  Both these multifactorial diseases involve the age-related accumulation of extracellular deposits, linked to dysregulation of protein homeostasis. Since the advent of the genome-wide association study (GWAS) many SNPs have been found to be associated with these two diseases. However the SNP in CST3, which translates into an amino acid change in the leader sequence of the precursor protein, is the first identified to increase the risk of developing both diseases. Moreover the authors demonstrate that the risk associated with the mutant allele follows the same recessive model for both diseases. Thus only those individuals with two copies of the mutant cystatin allele are at elevated risk of developing both diseases.