Project description:Investigate whether VLDLR can mediate the biogenesis of circular RNA, and whether an adaptor that bridges the VLDLR signal and the biogenesis of circular RNA .
Project description:Autophagy plays vital housekeeping neuronal functions but is not believed to fuel energy metabolism. Autophagy regulation by lipids nutrient sensors have not been identified. Cone photoreceptors’ very-low-density lipoprotein receptor (Vldlr) expression facilitates the uptake of triglyceride-derived fatty acid. In Vldlr-/- mice, we identify free fatty acid receptor 1 (Ffar1) as a suppressor of transcription factor EB (Tfeb), a master regulator of autophagy. Tfeb, in turn, governs the expression of PGC1 and Sirtuin-3, leading to reduced -ketoglutarate (-KG). We recently showed that low -KG in Vldlr-/- photoreceptors drives Vegfa expression and neovascularization reminiscent of a subset of age-related macular degeneration (AMD). Metabolomics of human AMD vitreous and Vldlr-/- retinas identified a similar Krebs cycle metabolite signature. Improving autophagy in AMD-like mice rescued the neovascular phenotype and vision. Dysregulated autophagy may therefore compound the energy failure of photoreceptors contributing to neovascular AMD and could be a driving force in other neovascular diseases.
Project description:Macular telangiectasia (MacTel) is a vision-threatening retinal disease with unknown pathogenesis and no approved treatment. Very low-density lipoprotein receptor mutant mice (Vldlr(-/-)) exhibit critical features of MacTel such as retinal neovascularization and photoreceptor degeneration. In this study, the authors evaluate the therapeutic potential of resveratrol, a plant polyphenol, in Vldlr(-/-) mice as a model for MacTel.Vldlr(-/-) and wild-type mice at postnatal day (P) 21 to P60 or P10 to P30 were treated orally with resveratrol. The number of neovascular lesions was evaluated on retinal flatmounts, and resveratrol effects on endothelial cells were assessed by Western blot for phosphorylated ERK1/2, aortic ring, and migration assays. Vegf and Gfap expression was evaluated in laser-capture microdissected retinal layers of angiogenic lesions and nonlesion areas from Vldlr(-/-) and wild-type retinas.From P15 onward, Vldlr(-/-) retinas develop vascular lesions associated with the local upregulation of Vegf in photoreceptors and Gfap in the inner retina. Oral resveratrol reduces lesion formation when administered either before or after disease onset. The reduction of vascular lesions in resveratrol-treated Vldlr(-/-) mice is associated with the suppression of retinal Vegf transcription. Resveratrol also reduces endothelial ERK1/2 signaling as well as the migration and proliferation of endothelial cells. Furthermore, a trend toward increased rhodopsin mRNA in Vldlr(-/-) retinas is observed.Oral administration of resveratrol is protective against retinal neovascular lesions in Vldlr(-/-) mice by inhibiting Vegf expression and angiogenic activation of retinal endothelial cells. These results suggest that resveratrol might be a safe and effective intervention for treating patients with MacTel.
Project description:We performed RNA-Seq analysis of neoatal rat ventricular cardiomyocytes (NRVCs)which were treated with Reelin,or knocking down Vldlr,Thbs1,or overexpressing Vldlr to investigate the moleclular mechanism of Thbs1/Reelin-Vldlr to regulate cardiomyocyte proliferation.In addition,the day 1mouse cardiomyocytes in Myh6-Cre;Vldlr f/f mice ,Myh6-Cre;Vldlr f/+ mice ,versus Vldlr f/f mice were also performed to explore the fucntion of Vldlr which regulating cardiomyocyte proliferation in vivo.
Project description:Transcription profiling by array of siRNA against Quaking (QKI) transcripts to identify transcripts that are modulated by QKI activity. MiR-155 is an oncogene and we report here that it targets QKI transcripts. Therefore, we believe that QKI acts as a tumor suppressor gene in different leukemias. We ablated the expression of QKI transcripts using siRNAs in order to further elucidate the effects of QKI in leukemogenesis, and how miR-155 and QKI functionally interact with each other.
Project description:Investigating the differential expression profile of circular RNA in ocular tissues derived from VLDLR deletion and Wild type mouse with t 75% oxygen treatment(postnatal day 7 to postnatal day 12)
Project description:To identify QKI targets, we performed QKI knockdown in BEAS2B cells and analyzed alternative splicing patterns by high-throughput RNA sequencing. The mRNA profiles of control- and QKI-knockdown BEAS2B cells were generated by deep sequencing using Illumina GAIIx sequencer.