• 679 Citations
  • 15 h-Index
20072019
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Personal profile

Research interests

The overall goal of the laboratory of Dr. Michael Dennis is to identify the molecular mechanisms and signaling pathways that contribute to altered gene expression patterns in disease states, with a particular emphasis on diabetes. Studies funded by the American Diabetes Association and National Institutes of Health have primarily focused on exploring the impact of post-translational modification (i.e., phosphorylation and O-GlcNAcylation) of eukaryotic translation initiation factors (eIFs) in mediating a shift from cap-dependent to cap-independent mRNA translation.

The Dennis laboratory has also actively explored regulation of the master kinase mammalian target of rapamycin (mTOR) and its impact on gene expression in response to nutrients and growth factors.

Recent publications demonstrate that whole body genetic ablation of the translational repressor 4E-BP1 or the stress response protein REDD1, which regulates 4E-BP1 action, is sufficient to prevent visual dysfunction in rodent models of type 1 diabetes. This is at least in part because 4E-BP1 and REDD1 regulate hyperglycemia-induced expression of the pro-angiogenic cytokine VEGF, which plays a major causal role in the development of the microvascular complications.

Elucidation of these translational control mechanisms is expected to validate new targets for the development of a new generation of therapeutics aimed at addressing the molecular basis of diabetic retinopathy.

While recently developed antibody-based therapeutics designed to block VEGF signaling have improved diabetic retinopathy treatment outcomes, up to half of patients fail to fully respond to anti-VEGF therapies. This is at least in part because VEGF levels poorly correlate with the extent of retinal edema, implying that additional factors are likely to play a role in disease pathology. The hope is that recently identified small molecule inhibitors may be used to counter diabetes-induced initiation factor defects, and thus not only prevent the increase in VEGF translation, but also impact the expression of other homeostatic and trophic factors in retina.

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  • 3 Similar Profiles
Phosphorylation Chemical Compounds
Retina Medicine & Life Sciences
Protein Biosynthesis Medicine & Life Sciences
Peptide Initiation Factors Medicine & Life Sciences
DNA Damage Medicine & Life Sciences
Proteins Medicine & Life Sciences
Hyperglycemia Medicine & Life Sciences
Leucine Medicine & Life Sciences

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Projects 2010 2018

Diabetic Retinopathy
Hyperglycemia
Retina
Gene Expression
Protein Biosynthesis
Diet
Gene Expression
Hyperglycemia
Liver
RNA Cap-Binding Proteins

Research Output 2007 2019

  • 679 Citations
  • 15 h-Index
  • 26 Article
  • 1 Chapter
  • 1 Comment/debate

O-GlcNAcylation alters the selection of mRNAs for translation and promotes 4E-BP1 dependent mitochondrial dysfunction in the retina

Dierschke, S. K., Miller, W. P., Favate, J. S., Shah, P., Kawasawa, Y. I., Salzberg, A. C., Kimball, S. R., Jefferson, L. S. & Dennis, M. D., Jan 1 2019, In : Journal of Biological Chemistry. 294, 14, p. 5508-5520 13 p.

Research output: Contribution to journalArticle

Protein Biosynthesis
Retina
Messenger RNA
Ribosomes
Eukaryotic Initiation Factors
1 Citation (Scopus)

REDD1 activates a ROS-generating feedback loop in the retina of diabetic mice

Miller, W. P., Toro, A. L., Barber, A. & Dennis, M., May 1 2019, In : Investigative Ophthalmology and Visual Science. 60, 6, p. 2369-2379 11 p.

Research output: Contribution to journalArticle

Open Access
Retina
Reactive Oxygen Species
Cysteine
Mitochondrial Membrane Potential
Hydrogen Peroxide
2 Citations (Scopus)

Consumption of a high fat diet promotes protein O-GlcNAcylation in mouse retina via NR4A1-dependent GFAT2 expression

Dai, W., Dierschke, S. K., Toro, A. L. & Dennis, M., Dec 1 2018, In : Biochimica et Biophysica Acta - Molecular Basis of Disease. 1864, 12, p. 3568-3576 9 p.

Research output: Contribution to journalArticle

Nuclear Receptor Subfamily 4, Group A, Member 1
High Fat Diet
Retina
Palmitates
Cell Culture Techniques
3 Citations (Scopus)

Deletion of the Akt/mTORC1 repressor REDD1 prevents visual dysfunction in a rodent model of type 1 diabetes

Miller, W. P., Yang, C., Mihailescu, M. L., Moore, J. A., Dai, W., Barber, A. J. & Dennis, M. D., Jan 1 2018, In : Diabetes. 67, 1, p. 110-119 10 p.

Research output: Contribution to journalArticle

Type 1 Diabetes Mellitus
Rodentia
Cell Death
Retina
Contrast Sensitivity
2 Citations (Scopus)

Deletion of the stress-response protein REDD1 promotes ceramide-induced retinal cell death and JNK activation

Dai, W., Miller, W. P., Toro, A. L., Black, A. J., Dierschke, S. K., Feehan, R. P., Kimball, S. & Dennis, M., Dec 1 2018, In : FASEB Journal. 32, 12, p. 6883-6897 15 p.

Research output: Contribution to journalArticle

Ceramides
Cell death
Nutrition
Heat-Shock Proteins
Thioredoxins