Omics Analyses in Keratoconus: from Transcriptomics to Proteomics

Cai, Jingwen; Estes, Amy; Liu, Yutao

doi:10.1007/s40135-020-00253-x

Cited by 11 publications

(8 citation statements)

References 87 publications

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“…Finally, the variants located in genes presented in two or more families and differentially expressed in KC were considered as candidate rare variants (Lee et al, 2009;Mace et al, 2011;Bykhovskaya et al, 2016;Kabza et al, 2017;Khaled et al, 2018;You et al, 2018;Sharif et al, 2019;Shinde et al, 2020;Sun et al, 2022). The STRING website was used to predict the relationships of proteins with previously reported genes in KC and known KCassociated pathways, including extracellular matrix organization, WNT signaling, Hippo signaling, focal adhesion and TGF-β pathways (Cai et al, 2020;Hao et al, 2021).…”

Section: Bioinformatics Analysismentioning

confidence: 99%

Family-based exome sequencing identifies candidate genes related to keratoconus in Chinese families

Yang

Yin

et al. 2022

Front. Genet.

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Background: Keratoconus (KC) is a complex corneal disorder with a strong genetic component. The present study aimed to identify candidate genes related to KC in Chinese families.Methods: Family-based exome sequencing was performed in ten patients suffering from KC who belong to five families with two affected members in each. The candidate rare variants were identified with multi-step bioinformatics analysis. The STRING website was used to perform the protein interaction of the identified genes.Results: Our analyses identified 32 candidate rare variants in 13 genes by family-based exome sequencing. The molecular analyses of identified genes showed that EPCAM directly interacted with CTNNB1 of the Hippo signaling pathway and focal adhesion pathway, and directly interacted with CTNNB1, CDH1 of the WNT signaling pathway. SHROOM3 directly interacted with ROCK2, ROCK1 of the focal adhesion pathway. SYNE1 directly interacted with MUSK of the extracellular matrix organization pathway. TEK directly interacted with VEGFA, SHC1, PIK3R1, GRB2 of the focal adhesion pathway. TTN directly interacted with CAPN3 of the extracellular matrix organization pathway.Conclusion: The EPCAM, SHROOM3, SYNE1, TEK, and TTN genes were potential high-risk candidate pathogenic genes of familial KC. The findings might significantly improve our understanding of the genetic etiology of the disease, providing novel insights on KC pathogenesis.

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Section: Bioinformatics Analysismentioning

confidence: 99%

Family-based exome sequencing identifies candidate genes related to keratoconus in Chinese families

Yang

Yin

et al. 2022

Front. Genet.

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“…A decrease in Nrf-2 may underlie the poor antioxidant functions in KC 14 , 42 , 43 . SF, an Nrf-2 activator, mitigates ROS accumulation in corneal stromal cells and enhances Nrf-2 nuclear translocation 39 , 44 . SF significantly reduced NO levels, increased SOD levels, and inhibited oxidative stress in HKs within the KC microenvironment.…”

Section: Discussionmentioning

confidence: 99%

Balanced activation of Nrf-2/ARE mediates the protective effect of sulforaphane on keratoconus in the cell mechanical microenvironment

Liu,

Ma,

Yan

2024

Sci Rep

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Keratoconus (KC) is a progressive degenerative disease that usually occurs bilaterally and is characterized by corneal thinning and apical protrusion of the cornea. Oxidative stress is an indicator of the accumulation of reactive oxygen species (ROS), and KC keratocytes exhibit increased ROS production compared with that of normal keratocytes. Therefore, oxidative stress in KC keratocytes may play a major role in the development and progression of KC. Here, we investigated the protective effect of sulforaphane (SF) antioxidants using a hydrogel-simulated model of the cell mechanical microenvironment of KC. The stiffness of the KC matrix microenvironment in vitro was 16.70 kPa and the stiffness of the normal matrix microenvironment was 34.88 kPa. Human keratocytes (HKs) were cultured for 24 h before observation or drug treatment with H2O2 in the presence or absence of SF. The levels of oxidative stress, nuclear factor E2-related factor 2 (Nrf-2) and antioxidant response element (ARE) were detected. The high-stress state of HKs in the mechanical microenvironment of KC cells compensates for the activation of the Nrf-2/ARE signaling pathway. H2O2 leads to increased oxidative stress and decreased levels of antioxidant proteins in KC. In summary, SF can reduce endogenous and exogenous oxidative stress and increase the antioxidant capacity of cells.

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“…There are likely many, but currently unknown, clinical implications of characterizing how CXL changes corneal tissue at the molecular and cellular levels. Wnt signaling modulation has been reported in KCs [ 19 , 33 , 35 , 36 ], largely focused on the epithelium and through RNA-Seq approaches. Interestingly, Cuellar-Partida linked an exonic Wnt10A variant to the central corneal thickness.…”

Section: Discussionmentioning

confidence: 99%

Collagen Crosslinking for Keratoconus: Cellular Signaling Mechanisms

et al. 2023

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Collagen crosslinking (CXL) is a widely used treatment to halt the progression of keratoconus (KC). Unfortunately, a significant number of patients with progressive KC will not qualify for CXL, including those with corneas thinner than 400 µm. The present study aimed to investigate the molecular effects of CXL using in vitro models, mirroring the normal, as well as thinner corneal stroma seen in KCs. Primary human corneal stromal cells were isolated from healthy (HCFs) and keratoconus (HKCs) donors. Cells were cultured and stimulated with stable Vitamin C resulting in 3D self-assembled extracellular matrix (ECM), cell-embedded, constructs. CXL was performed on (a) thin ECM with CXL performed at week 2 and (b) normal ECM with CXL performed at week 4. Constructs without CXL served as controls. All constructs were processed for protein analysis. The results showed modulation of Wnt signaling, following CXL treatment, as measured by the protein levels of Wnt7b and Wnt10a, correlated to the expression of α-smooth muscle actin (SMA). Further, the expression of a recently identified KC biomarker candidate, prolactin-induced protein (PIP), was positively impacted by CXL in HKCs. CXL-driven upregulation of PGC-1 and the downregulation of SRC and Cyclin D1 in HKCs were also noted. Although the cellular/molecular impacts of CXL are largely understudied, our studies provide an approximation to the complex mechanisms of KC and CXL. Further studies are warranted to determine factors influencing CXL outcomes.

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Omics Analyses in Keratoconus: from Transcriptomics to Proteomics

Cited by 11 publications

References 87 publications

Family-based exome sequencing identifies candidate genes related to keratoconus in Chinese families

Family-based exome sequencing identifies candidate genes related to keratoconus in Chinese families

Balanced activation of Nrf-2/ARE mediates the protective effect of sulforaphane on keratoconus in the cell mechanical microenvironment

Collagen Crosslinking for Keratoconus: Cellular Signaling Mechanisms

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