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Vitreous proteome of transgenic INSC94Y pigs compared to wild type

ABSTRACT: INSC94Y transgenic pigs serve as a valuable model for permanent neonatal diabetes mellitus. Through genetically engineered modifications in the insulin (INS) gene, this model presents with impaired insulin secretion, resulting elevated fasting blood-glucose levels (hyperglycemia) [1].One of the severe complications of diabetes mellitus are hypoglycemia-mediated morphological abnormalities in the retina, also described as diabetic retinopathy (DR). Adjacent to the retina lies the vitreous, a gelatinous, highly hydrated matrix, which is important for ocular function and retinal physiology. It contains variety of proteins and signaling molecules, which are useful for the characterization of the biological activity of the vitreous itself, and may help to elucidate molecular processes occurring in the retina, especially under pathophysiological conditions and in disease. To gain insight into the proteomic profile of porcine vitreous and detect possible differences relevant to DR pathogenesis, we used discovery proteomics for analysis of INSC94Y vitreous compared to wild-type controls. Reference: [1] Renner, S.; Braun-Reichhart, C.; Blutke, A.; Herbach, N.; Emrich, D.; Streckel, E.; Wunsch, A.; Kessler, B.; Kurome, M.; Bahr, A.; et al. Permanent neonatal diabetes in INS(C94Y) transgenic pigs. Diabetes 2013, 62, 1505-1511, doi:10.2337/db12-1065.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Sus Scrofa Domesticus (domestic Pig)

TISSUE(S): Vitreous Humor

DISEASE(S): Permanent Neonatal Diabetes Mellitus

SUBMITTER: Roxane Degroote

LAB HEAD: Stefanie M Hauck

PROVIDER: PXD038198 | Pride | 2024-08-27

REPOSITORIES: Pride

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			Action	DRS
	HAU9261A10MA9__010-S745_WT_GK_li_HAU9261A10MA9-40-322510.raw	Raw
	HAU9261A11MA9__011-S99_WT_GK_re_HAU9261A11MA9-40-322604.raw	Raw
	HAU9261A12MA9__012-S99_WT_GK_li_HAU9261A12MA9-40-322611.raw	Raw
	HAU9261A15MA9__015-S100_diab_GK_re_HAU9261A15MA9-40-322622.raw	Raw
	HAU9261A16MA9__016-S100_diab_GK_li_HAU9261A16MA9-40-322628.raw	Raw

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Project description:Reduced oxygenation of photoreceptors and the RPE in the ageing eye may be a risk factor for the development of both neovascular and dry AMD. Chronic activation of the molecular response to hypoxia in RPE or photoreceptors leads to retinal degeneration that depends on hypoxia inducible transcription factors. For approaching the identification of accessible markers characteristic for photoreceptors with an activated hypoxic response, we used a proteomics approach to determine the protein composition of the vitreous humor in mice. To discriminate between rod and cone-specific effects we used genetically modified mice that had the hypoxic response activated specifically in rods of a rod-dominant retina (rodΔVhl) or a genetically engineered all-cone retina (coneΔVhl). For comparison, we used wild-type mice exposed for 6 hours to acute hypoxia. We identified 1,357 unique proteins in the vitreous of mice after acute hypoxia, 1,624 in rodΔVhl and 1,895 in coneΔVhl mice. Of these, 1,043 proteins were common to all three types of mice. Of the identified proteins, 257 were significantly regulated by a factor of 1.5 or more in hypoxic mice, 258 in rodΔVhl and 356 in coneΔVhl mice in at least one of the three analyzed time points. Only 51 of the significantly regulated proteins were common to the vitreous of rodΔVhl and coneΔVhl mice, suggesting different consequences of the activated hypoxic response for rods and cones. Guanylate binding protein 2 (GBP2) was found at increased levels in the vitreous of both rodΔVhl and coneΔVhl mice at all time points tested. This was also reflected by increased gene expression in the retina. Although retinal expression of the AMD-associated gene alpha-2 macroglobulin (A2M) appeared increased in both types of mice, the protein was only found elevated in the vitreous of rodΔVhl mice. Other proteins found increased included Serpina3n, synaptosome associated protein 25 (SNAP25) and others. The distinct protein compositions present at early and late time points, suggest a well-regulated process in our models. We hypothesize that some of the proteins identified at early time points may potentially be used as markers for the chronic hypoxic response of photoreceptors.

Project description:PURPOSE: To investigate the circulatory microRNA (miRNA) profiles of aqueous, vitreous, and plasma in order to identify biomarkers in aqueous humor or plasma that are reflecting changes in vitreous of patients with diabetes. METHODS: Aqueous, vitreous and plasma samples were collected from a total of 27 patients - 11 controls (macular pucker or macular hole patients) and 16 patients with diabetes mellitus (DM) undergoing vitreoretinal surgery: DM-Type I with proliferative diabetic retinopathy (PDR) (DMI-PDR), DM Type II with PDR (DMII-PDR) and DM Type II with nonproliferative DR (DMII-NPDR). MiRNAs were isolated using Qiagen microRNeasy kit, quantified on BioAnalyzer, labeled with FlashTag kit, and profiled on Affymetrix GeneChip miRNA 3.0 microarrays. Data analysis was done using Expression Console (EC), Transcriptome Analysis Console (TAC), and Ingenuity Pathway Analysis (IPA) software. RESULTS: Our comparison of circulatory miRNA population of aqueous and vitreous humor and plasma showed that out of total of 847 human miRNA probes on the Affymetrix GeneChip miRNA 3.0 we found common miRNAs for both aqueous and vitreous samples, as well as larger number of unique miRNA, dependent on the DM type and presence of retinopathy. Most of the dysregulated miRNAs in aqueous and vitreous of DM patients were upregulated, while in plasma, most of the DM-specific miRNAs were downregulated. Dysregulation of miRNAs in aqueous generally do not appear to be a good representative of the miRNA abundance in vitreous, or plasma, although we did identify a few candidates for common biomarkers: let-7b, miR-320b, miR-762 and miR-4488. Additionally, each of the DR subtypes showed a set of miRNA that is uniquely dysregulated in each fluid, for example in aqueous samples for DMII-NPDR it was miR-455-3p, for DMII-PDR was miR-296, and for DMI-PDR it was miR-3202. Pathway analysis identified TGF-beta and VEGF pathways as the common targets for miRNAs dysregulated in DR aqueous and vitreous. CONCLUSIONS: The comparative profiling of circulatory miRNAs in aqueous, vitreous, and plasma showed that a small number of circulatory miRNAs displayed differential presence in controls vs. diabetic retinopathy. A pattern is emerging of sets of miRNA that are common or uniquely dysregulated in the blood plasma or ocular fluids of DR subtypes, offering promise for the use of ocular fluids and plasma for identifying diagnostic and therapeutic targets.

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Vitreous proteome of transgenic INSC94Y pigs compared to wild type

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