A multistep validation process of biomarkers for preclinical drug development

Freeman, Willard M.; Bixler, Georgina V.; Brucklacher, Robert M.; Lin, Cheng‐mao; Patel, Kruti M.; VanGuilder, Heather D.; LaNoue, Kathryn F.; Kimball, Scot R.; Barber, Alistair J.; Antonetti, David A.; Gardner, Thomas W.; Bronson, Sarah K.

doi:10.1038/tpj.2009.60

Cited by 26 publications

(40 citation statements)

References 40 publications

(61 reference statements)

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“…We have previously demonstrated that all of these genes are differentially expressed in the retina after 3 months of uncontrolled diabetes in multiple independent cohorts of animals and that the dysregulation occurs after different periods of hyperglycemia and loss of insulin signaling. In timecourse experiments examining 2 weeks, 1 month, and 3 months of uncontrolled diabetes, we demonstrated that changes in expression occur as early as two weeks (C1inh, C1s, Carhsp1, Chi3L1, End2, Gbp2, Hspb1, Jak3, Kcne2, Lama5, Lgals3, Lgals3bp, Nppa, Pedf, Timp) or at some time after 1 month and before 3 months (Ccr5, Dcamkl1, Ednrb, Icam1, Mct1, Pcgf1, Slc6a11, Stat3, Tnfrsf12a) (Freeman et al, 2010). In agreement with previous findings, all biomarker transcripts were differentially expressed (ANOVA, BH-MTC) with the exceptions of Ednrb, Lama5, Pcgf1, and Pedf which did not reach significance and pass multiple testing correction (Supplemental Table 1, Figure 4a).…”

Section: Resultsmentioning

confidence: 79%

“…We have previously reported a set of diabetes-associated retinal gene expression biomarkers for use in monitoring interventions seeking to reverse the diabetic phenotype in rat models of diabetes (Freeman et al, 2010). This 24 gene set encompasses genes related to inflammation, vascular function, and neuronal signaling (Table 2).…”

Section: Resultsmentioning

confidence: 99%

“…Longitudinal assessment of in vivo retinal gene expression is not possible within one animal, but analysis of the mRNA expression of previously described diabetic retina biomarker genes from this animal model (Freeman et al, 2010) provides additional context for the effects of differing histories of insulin therapy on retinal phenotype. These gene expression changes have been demonstrated to occur quickly, as early as 2 weeks of uncontrolled diabetes (C1inh, C1s, Carhsp1, Chi3L1, End2, Gbp2, Hspb1, Jak3, Kcne2, Lama5, Lgals3, Lgals3bp, Nppa, Pedf, Timp) or after a longer duration of uncontrolled diabetes [greater than 1 month and less than 3 months (Ccr5, Dcamkl1, Ednrb, Icam1, Mct1, Pcgf1, Slc6a11, Stat3, Tnfrsf12a)].…”

Section: Discussionmentioning

confidence: 99%

“…This study sought to examine whether specific measures of whole animal physiology, retinal neuroinflammation and synaptic maintenance demonstrate metabolic memory using a model that we have previously reported to demonstrate molecular changes consistent with the metabolic memory phenotype (Bixler et al, 2011; Brucklacher et al, 2008; Freeman et al, 2010). …”

Section: Introductionmentioning

confidence: 99%

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Insulin treatment normalizes retinal neuroinflammation but not markers of synapse loss in diabetic rats

Masser¹,

Starkey²,

Bixler³

et al. 2014

Experimental Eye Research

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Diabetic retinopathy is one of the leading causes of blindness in developed countries, and a majority of patients with type I and type II diabetes will develop some degree of vision loss despite blood glucose control regimens. The effects of different insulin therapy regimens on early metabolic, inflammatory and neuronal retinal disease processes such as retinal neuroinflammation and synapse loss have not been extensively investigated. This study compared 3 months non-diabetic and streptozotocin (STZ)-induced diabetic Sprague Dawley rats. Diabetic rats received either no insulin treatment, systemic insulin treatment beginning after 1 week uncontrolled diabetes (early intervention, 11 weeks on insulin), or after 1.5 months uncontrolled diabetes (late intervention, 6 weeks on insulin). Changes in both whole animal metabolic and retinal inflammatory markers were prevented by early initiation of insulin treatment. These metabolic and inflammatory changes were also normalized by the later insulin intervention. Insulin treatment begun 1 week after diabetes induction ameliorated loss of retinal synapse markers. Synapse markers and presumably synapse numbers were equivalent in uncontrolled diabetes and when insulin treatment began at 1.5 months of diabetes. These findings are in agreement with previous demonstrations that retinal synapses are lost within 1 month of uncontrolled diabetes and suggest that synapses are not regained with glycemic control and restoration of insulin signaling. However, increased expression of metabolic and inflammatory markers associated with diabetes was reversed in both groups of insulin treatment. This study also emphasizes the need for insulin treatment groups in diabetic retinopathy studies to provide a more faithful modeling of the human condition.

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Section: Resultsmentioning

confidence: 79%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Insulin treatment normalizes retinal neuroinflammation but not markers of synapse loss in diabetic rats

Masser¹,

Starkey²,

Bixler³

et al. 2014

Experimental Eye Research

View full text Add to dashboard Cite

show abstract

“…Coordinated phosphorylation and dephosphorylation of CARHSP1 contribute to the multiple phosphorylated isoforms of CARHSP1 in acinar cells (9). Recently, CARHSP1 was discovered as a biomarker for diabetic retinopathy (10) and as a regulator of TNF-␣ mRNA stability in macrophages (11). CARHSP1 may be involved in oxidative stress via traffic between stress granules and processing bodies (12).…”

mentioning

confidence: 99%

Inhibition of Gluconeogenic Genes by Calcium-regulated Heat-stable Protein 1 via Repression of Peroxisome Proliferator-activated Receptor α

Fan

Guo

Hamblin

et al. 2011

Journal of Biological Chemistry

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Critical role of endoplasmic reticulum stress in chronic endothelial activation−induced visual deficits in tie2‐tumor necrosis factor mice

Lenin

Nagy

Alli

et al. 2018

J of Cellular Biochemistry

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Diabetic retinopathy (DR) is the leading cause of vision loss among working-age adults. The interplay between hyperglycemia and endothelial activation in inducing endoplasmic reticulum (ER) stress pathways and visual deficits in DR is not fully understood. To address this, we used a mouse model of chronic vascular activation using endothelial-specific tumor necrosis factor-α (TNF-α)-expressing (tie2-TNF) mice to induce diabetes with streptozotocin. At 4 weeks post streptozotocin, a significant 2-fold to 10-fold increase in retinal neurovascular inflammatory gene transcript response in tie2-TNF mice was further increased in diabetic tie2-TNF mice. A decrease in visual acuity and scotopic b-wave amplitude in tie2-TNF mice was further accentuated in diabetic tie2-TNF mice and these changes correlated with a multi-fold increase in retinal ER stress markers and a reduction in adherens junctions. Cultured retinal endothelial cells showed a significant decrease in trans-endothelial resistance as well as VE-cadherin expression under TNF-α and high glucose stress. These changes were partly rescued by tauroursodeoxycholic acid, a potent ER stress inhibitor. Taken together, constant endothelial activation induced by TNF-α further exacerbated by hyperglycemia results in activation of ER stress and chronic proinflammation in a feed forward loop ultimately resulting in endothelial junction protein alterations leading to visual deficits in the retina. Inhibition of ER stress and endothelial activation may prove to be a novel therapeutic target in DR.

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A multistep validation process of biomarkers for preclinical drug development

Cited by 26 publications

References 40 publications

Insulin treatment normalizes retinal neuroinflammation but not markers of synapse loss in diabetic rats

Insulin treatment normalizes retinal neuroinflammation but not markers of synapse loss in diabetic rats

Inhibition of Gluconeogenic Genes by Calcium-regulated Heat-stable Protein 1 via Repression of Peroxisome Proliferator-activated Receptor α

Critical role of endoplasmic reticulum stress in chronic endothelial activation−induced visual deficits in tie2‐tumor necrosis factor mice

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