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Large-Scale Quantitative Proteomics of Retinal Mitochondrial Fractions from Age-Related Macular Degeneration (AMD) Patients

ABSTRACT: Age-related macular degeneration (AMD) is the leading cause of blindness in seniors, with no effective treatment options available for most patients. AMD is characterized by the death of retinal pigment epithelium (RPE) and photoreceptors, resulting in central vision loss causing tremendous difficulties in performing daily tasks requiring visualization of fine details visualization. Dysfunction of RPE mitochondria is a critical early event involved in AMD pathogenesis, and we previously reported that maintaining normal mitochondrial functions in RPE could be a viable option for AMD treatment. We hypothesize that dysregulation of RPE mitochondrial proteome is highly relevant to the loss of RPE mitochondrial function during the transition from healthy aging to early AMD. The hypothesis was examined by quantitative proteomics using UHR-IonStar.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Retina

SUBMITTER: Shichen Shen

LAB HEAD: Jun Qu

PROVIDER: PXD033413 | Pride | 2022-07-13

REPOSITORIES: Pride

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			Action	DRS
	210501_UMN_Mito_01_S1_MGS1_2_240k_clm177_WC18_65cm_HCD_OT_AGtrap_val50_180min_8ul.mzid.gz	Mzid
	210501_UMN_Mito_01_S1_MGS1_2_240k_clm177_WC18_65cm_HCD_OT_AGtrap_val50_180min_8ul.raw	Raw
	210501_UMN_Mito_02_MGS2_47_240k_clm177_WC18_65cm_HCD_OT_AGtrap_val50_180min_4ul.raw.mzXML	Mzxml
	210501_UMN_Mito_02_S2_MGS2_26_240k_clm177_WC18_65cm_HCD_OT_AGtrap_val50_180min_4ul.mzid.gz	Mzid
	210501_UMN_Mito_02_S2_MGS2_26_240k_clm177_WC18_65cm_HCD_OT_AGtrap_val50_180min_4ul.raw	Raw

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Project description:Age-related macular degeneration (AMD) is a leading cause of blindness. Most vision loss occurs following the transition from a disease of deposit formation and inflammation to a disease of neovascular fibrosis and/or cell death. Here, we investigate how protracted wound stimulus leads to seminal changes in gene expression and the onset of a self-sustained state of wound response in retinal pigmented epithelial (RPE) cells. Using a human fetal RPE cell culture model and a systems level transcriptome analysis, we show that prolonged subconfluent culture resulting from repeated passage, leads to terminal acquisition of a mesenchymal-like phenotype post-confluence accompanied by altered expression of >40% of the transcriptome. In contrast, at subconfluence <5% of transcripts have >2-fold expression changes after repeated passage. Protein-protein interaction analysis reveals a core set of genes comprising two interconnected modules with functions pertaining to wound response and cell division. Among the wound response genes are the TGF-beta pathway activators: TGFB1, TGFG2, INHBA, INHBB, GDF6, CTGF, and THBS1. Small molecule inhibition of TGFBR1/ACVR1B mediated signaling both forestalls and reverses the passage-dependent loss of epithelial potential. Moreover, a disproportionate number of RPE wound response genes have altered expression in neovascular and geographic AMD; including key members of the TGF-beta pathway. In conclusiton, in RPE cells the switch to a terminal mesenchymal-like state following protracted or repeated wound stimulus is driven by activation of a self-perpetuating TGF-beta feedback loop. Targeted inhibition of TGF-beta signaling may be an effective approach towards retarding AMD progression and producing RPE cells in quantity for research and cell based therapies. Transcriptome profiles were determined from 44 human fetal RPE cultures of varying passage number, seeding density, culture maturity, and/or growth factor or small molecule treatment. Probes were labeled with Cy3 or Cy5 and Agilent whole genome microarrays were hybridized with a pair of Cy3 and Cy5 probes. After background subtraction and LOWESS correction to adjust for dye-dependent effects the net intensity values were determined as described in the Data Processing section and the entire data set was quantile normalized. The values reported in the Series Matrix are the quantile normalized net intensity values of the gene specific probes.

Dataset Information

Large-Scale Quantitative Proteomics of Retinal Mitochondrial Fractions from Age-Related Macular Degeneration (AMD) Patients

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