Dataset Information

Corneal protome of trangenic TGFBI R124H mouse model

ABSTRACT: In this study we analysed the proteome of transforming growth factor β-induced protein (TGFBIp) R124H transgenic mouse corneas in an attempt to understand the disease mechanisms leading to the granular corneal dystrophy type 2. The transgenic mouse model was generated by insertion of human TGFBI cDNA with the R124H mutation into the first exon of the mouse TGFBI DNA generating the transgenic TGFBIR124H mouse model We compared the corneal proteome of three wild-type, heterozygous, and homozygous mice of different genders, which were age-matched and analysed the proteolytic processing and relative amount of TGFBIp. No protein deposits were observed in the investigated corneas.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Cornea

SUBMITTER: Marie Vestergaard Lukassen

LAB HEAD: Jan J. Enghild

PROVIDER: PXD012902 | Pride | 2020-10-20

REPOSITORIES: Pride

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Publications

Protein Analysis of the TGFBI<sup>R124H</sup> Mouse Model Gives Insight into Phenotype Development of Granular Corneal Dystrophy.

Lukassen Marie V MV Poulsen Ebbe T ET Donaghy Jack J Mogensen Emilie H EH Christie Kathleen A KA Roshanravan Hila H DeDioniso Larry L Nesbit M Andrew MA Moore Tara T Enghild Jan J JJ

Proteomics. Clinical applications 20200706 6

<h4>Purpose</h4>Mutations in the transforming growth factor β-induced protein (TGFBIp) are associated with TGFBI-linked corneal dystrophies, which manifests as protein deposits in the cornea. A total of 70 different disease-causing mutations have been reported so far including the common R124H substitution, which is associated with granular corneal dystrophy type 2 (GCD2). The disease mechanism of GCD2 is not known and the current treatments only offer temporary relief due to the reoccurrence of ...[more]

PMID: 32558206

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Project description:Purpose: Klf5 plays a critical role in the mouse ocular surface (Kenchegowda et al., 2011. Dev Biol. 356:5-18). Here, we compare wild-type (WT) and Klf5-conditional null (Klf5CN) corneal gene expression at postnatal day-11 (PN11) and PN56 to identify the Klf5-target genes. Methods: Gene expression was compared using Affymetrix microarrays with QPCR validation. Transient transfection assays examined the effect of Klf5 on selected target gene promoter activities. Whole-mount corneal immunofluorescent staining examined neovascularization and CD45+ macrophage influx. Results: Expression of 714 and 753 genes was increased, and 299 and 210 genes decreased in PN11 and PN56 Klf5CN corneas, respectively, with 366 concordant increases, 72 concordant decreases and 3 discordant changes. Canonical pathway analysis identified 35 and 34 significantly (p<0.001) enriched pathways at PN11 and PN56, respectively, with 24 common pathways. PN56 Klf5CN corneas shared 327 increases and 91 decreases with the previously described Klf4CN corneas (Swamynathan et al., 2008. IOVS 49:3360-70). Angiogenesis and immune response-related genes were affected consistent with lymphangiogenesis and macrophage influx in Klf5CN corneas, respectively. Expression of 1574 genes was increased and 1915 decreased, in the WT PN56 compared with PN11 corneas. Expression of many collagens, matrix metalloproteinases and other extracellular matrix associated genes decreased in WT corneas between PN11 and PN56, while that of solute carrier family members increased. Conclusions: Differences in PN11 and PN56 corneal Klf5-target genes reveal dynamic changes in Klf5 functions during corneal maturation. Klf4- and Klf5-target genes do not overlap, consistent with their non-redundant roles in the mouse cornea. Wild type and Klf5-conditional null mouse corneal gene expression at postnatal day-11 and -56 was compared by Affymetrix mouse whole genome 430 2 arrays. Four age-matched PN56 WT and Klf5CN mice, and 3 age-matched PN11 WT and Klf5CN mice each were used for comparison of corneal gene expression by microarrays. Two dissected corneas from each mouse were pooled for isolation of total RNA using the RNeasy Mini kit (Qiagen, Germantown, MD). The quality and integrity of the isolated total RNA was confirmed using an Agilent Bioanalyzer. Total RNAs were amplified and labeled using a 3' IVT Express Kit (Affymetrix Inc., Santa Clara, CA), and hybridized to Affymetrix MG 430 2 chips following the protocol suggested by the manufacturer.

Dataset Information

Corneal protome of trangenic TGFBI R124H mouse model

Publications

Protein Analysis of the TGFBI<sup>R124H</sup> Mouse Model Gives Insight into Phenotype Development of Granular Corneal Dystrophy.

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