October 2024- Research featured on diabeteBio Podcast.
Recent research in the lab was featured in on diabetes podcast.
September 2024- Age-related macular degeneration paper published in GeroScience.
These studies support a role for the stress response protein REDD1 in neurodegeneration in the context of AMD.
Congrats Sandeep!
August 2024- Kidney disease paper published in Diabetes.
These studies identify key signaling events that lead to podocyte loss in the kidney and renal function deficits caused by diabetes.
Congrats Sid!
July 2024- Children’s Miracle Network Funds Trainee Research Grant
This $50K award will fund studies to explore the molecular cause of kidney complications in juvenile diabetes.
Congrats Sid!
June 2024- Diabetic Heart Disease Paper Published in IJMS.
This paper identifies signaling pathways that contribute to cardiac function deficits in diabetic mice.
Congrats Shaunaci!
May 2024- BrightFocus Foundation funds Dr. Subramanian’s Postdoctoral Fellowship
This fellowship will explore the role of REDD1 in RPE injury leading to geographic atrophy.
Congrats Sandeep!
April 2024- JDRF funds Innovative Award to study diabetic complications!
New study funded to examine REDD1 allostery in the kidney and retina
March 2024- IOVS publishes NLRP3 paper
New study explores NLRP3 Inflammasome Priming in the Retina of Diabetic Mice
Congrats Chris!
February 2024- Dr. Yerlikaya receives service award.
Esma was honored with The Purpose Award for Senior Students from the Diverse Graduate Student Group (DGSG).
Congrats Esma!
January 2024- NIH funds R21!
National Eye Institute funds new project to explore a role for REDD1 in age-related macular degeneration.
December 2023- ADA funds Dr. Sunilkumar’s Postdoctoral Fellowship to study diabetic kidney disease
More on the Award in Penn State Health News.
Congrats Sid!
November 2023- Esma receives Patrick G. Quinn Award
Esma received the Patrick G. Quinn award for most outstanding post-candidacy doctoral student in the department of Cellular and Molecular Physiology.
Congrats Esma!
July 2023- Research Award received to study immune cells in kidney
Dr. Sunilkumar received the 2023 Finkelstein Memorial Trainee Research Award to examine a role for REDD1-dependent renal immune response in diabetic nephropathy.
Congrats Sid!
June 2023- GSK3 paper published at JBC
Our manuscript entitled “REDD1-dependent GSK3β dephosphorylation promotes NF-κB activation and macrophage infiltration in the retina of diabetic mice” was accepted for publication. Learn more HERE.
Congrats Sid!
April 2023- AJP features Heart Paper as Top Article!
Our manuscript entitled “PERK/ATF4-dependent expression of the stress response protein REDD1 promotes proinflammatory cytokine expression in the heart of obese mice” was highlighted as a trending article by the American Journal of Physiology-Endocrinology and Metabolism.
Congrats Shaunaci!
March 2023- CHS funds two Microgrants!
Penn State College of Medicine Comprehensive Health Studies (CHS) Program awarded the laboratory 2 seed grants to support new pilot studies:
– Siddharth Sunilkumar (PI) received seed funds to study mechanisms of diabetic kidney disease.
– Sandeep Subrahmanian (PI) received funds to explore age-related macular degeneration.
Congrats Sid and Sandeep!
Lab members win Spring 2023 Travel Awards!
Christopher McCurry and Esma Yerlikaya both received the Joseph M. and Eula C. Lawrence Travel Grant from the Retina Research Foundation and the Morgan Travel Award from the Department of Cellular and Molecular Physiology to attend the Association for Research in Vision and Ophthalmology 2023 Annual Conference.
Congrats Chris and Esma!
December 2022- Retinal inflammation paper published in JBC.
This manuscript provides new mechanistic insight into how diabetes promotes retinal inflammation and supports a working model wherein the stress response protein REDD1 acts to sustain activation of canonical NF-kB signaling.
Learn more about this study HERE.
Congrats Sid!
November 2022- Heart paper accepted at AJP-Endo Met.
This study identifies REDD1 as a missing molecular link that connects the development of endoplasmic reticulum stress in the hearts of obese mice with enhanced production of inflammatory cytokines.
Congrats Shaunaci!
October 2022- SYK paper published in IOVS
This research supports TREM2/DAP12 receptor-adaptor complex signaling via spleen tyrosine kinase (SYK) to promote stabilization of the transcription factor HIF-1α and increased angiogenic cytokine production by Müller glia in the retina of diabetic mice.
Learn more about this study HERE.
Congrats Esma!
September 2022- Redox Switch paper accepted at Diabetes
This manuscript reveals redox regulation of REDD1 and demonstrates a role for a REDD1 disulfide switch in development of oxidative stress in diabetic retinopathy.
Congrats Bill!
August 2022- Kidney Paper published in Diabetes
This manuscript demonstrates a role for REDD1-dependent GSK3 activation in the development of diabetes-induced oxidative stress and glomerular injury.
Learn more about this study HERE.
Congrats Sid!
July 2022- NHLBI funds F31!
This pre-doctoral NRSA fellowship is to investigate the hypothesis that REDD1 plays a maladaptive role in the pathogenesis of heart disease by augmenting the development of oxidative stress and inflammation in cardiomyocytes.
Congrats Shaunaci!
June 2022- Dr. Sunilkumar receives “Post-doc of the Year Award” from Penn State College of Medicine Postdoctoral Society.
Congrats Sid!
May 2022- Manuscript featured on cover of Diabetes
Müller glial expression of REDD1 is required for retinal neurodegeneration and visual dysfunction in diabetic mice. 2022 May 1;71(5):1051-1062. doi: 10.2337/db21-0853.
Learn more about this study HERE.
Congrats Bill and Allyson!
Lab Members win Spring 2022 Awards!
Bill received a Biomedical Sciences Graduation Award, Sid received a Departmental Postdoctoral Travel Award, and Shaunaci received a Morgan Travel Award.
Congrats!
December 2021- Dr. Miller graduates from the Biomedical Sciences PhD program and receives Karl H. Beyer Jr. PhD Scholarship.
Congrats Bill!
September 2021- NEI funds R01!
New project funded to explore redox-modification of REDD1 and its impact on oxidative stress and inflammation in diabetic retinopathy.
June 2021- Dr. Sunilkumar receives Children’s Miracle Network Trainee Research Grant
Congrats Sid!
May 2021- Dr. Dennis receives tenure and promotion to Associate Professor.
Congrats Michael!
April 2021- Glucagon Paper published in Cell Signal.
Congrats to Sid!
These studies provide evidence that glucagon elicits biphasic regulation of mTORC1. The unexpected acute activation of mTORC1/2 signaling by glucagon was associated with an increase in cAMP, dependent on EPAC signaling, and occurred concomitant with an increase in Rap1-GTP loading. These observations are consistent with a growing body of evidence that supports an expanded role for GCG action beyond its traditional role during fasting and hypoglycemia as an opposing signal to insulin. It is tempting to speculate that the findings may offer a potential foundation to understanding some of the surprising benefits of glucagon pharmacotherapy in diabetes.
Lab Members win Spring 2021 Awards!
Sid received the ASBMB Postdoctoral Researcher Award and Bill received the Graduate Alumni Society Award. Congrats!
Two New Diabetic Retinopathy Reviews
published Spring 2021.
December 2020- Rbp4 mRNA translation paper published in AJP- Endo Met.
Congrats Jackie!
RBP4 plays a critical role in development of metabolic disease and visual dysfunction, yet relatively little is known about the mechanisms that regulate its production. Herein we provide evidence for translational control of RBP4 synthesis. We demonstrate that activation of the nutrient-sensitive kinase mTORC1 promotes Rbp4 mRNA translation. The findings support the possibility that targeting Rbp4 mRNA translation represents an alternative to current therapeutic interventions that lower serum RBP4 concentration by promoting urinary excretion of the protein.
November 2020- NIH funds Research Supplement.
Congrats Shaunaci!
May 2020- Dr. Dierschke graduates and publishes CD40 paper in JBC.
Congrats to Sadie for finishing up her dissertation research and successfully defending!
May 2020- Nrf2 paper published in JBC.
Congrats Bill!
The transcription factor Nrf2 plays an important role in combating oxidative stress by promoting the expression of an array of antioxidant genes. Both individuals with diabetes and preclinical diabetes models exhibit evidence of a defect in retinal Nrf2 activation. Bill’s findings support an exciting new model wherein hyperglycemia-induced REDD1 blunts the Nrf2 antioxidant response to diabetes by activating GSK3, which in turn, phosphorylates Nrf2 to promote its degradation.
February 2020- Ang1-7 signaling paper published in IOVS.
Congrats Sadie!
The aim of this study was to investigate the impact of the renin-angiotensin system on retinal protein O-GlcNAcylation. Sadie found that in the retina of mice fed a high fat diet, retinal protein O-GlcNAcylation was augmented. However, mice receiving an ACE inhibitor in combination with the high fat diet, did not exhibit the effect. Notably, the beneficial effect of ACE inhibition was mediated by Ang1-7 signaling to inhibit O-GlcNAc Transferase Activity.
April 2020- National Institutes of Health fund F31!
Congrats Bill!
This 3-year pre-doctoral fellowship from the National Eye Institute is designed to investigate the hypothesis that REDD1 inhibits the endogenous antioxidant response to diabetes in retina by suppressing the synthesis and stability of nuclear factor erythroid-2-related factor 2 (Nrf2).
September 2019- National Institutes of Health fund R01!
This 5-year grant from the National Eye Institute is designed to address a fundamental gap in understanding of the molecular events that produce changes in protein expression within Müller glia leading to the loss of retinal homeostasis in diabetes. The project will investigate the impact of diabetes on the selection of mRNAs for translation in genetically identified Müller cells within the intact retina using a novel RiboTag mouse model.
May 2019- Dr. Dennis receives Samuel Hinkle Junior Faculty Research Award.
Congrats Michael!
This award recognizes the work of an Assistant Professor within five years of appointment to Penn State, demonstrating significant growth and impact in research. Dr. Dennis was recognized for his contributions to the field of diabetic retinopathy.
May 2019- William receives Patrick G. Quinn Award
This award recognizes Outstanding Performance by a Post-Comprehensive PhD Candidate in the Department of Cellular and Molecular Physiolgy.
Congrats Bill!
March 2019- Research Highlighted by Oregon Eye Health
May 2019- William passes comprehensive exam and gets paper published in IOVS.
Congrats Bill!
This study was designed to evaluate the role of the stress response protein REDD1 in diabetes-induced retinal pathology. In the retina of diabetic mice, REDD1 expression and reactive oxygen species (ROS) were increased and REDD1 deletion prevented diabetes-induced ROS. In R28 retinal cells in culture, hyperglycemic conditions enhanced REDD1 expression, the mitochondrial membrane potential, and ROS levels. However, similar effects were not observed in retinal cells lacking REDD1. In REDD1-deficient cells, dominant negative Akt or constitutively active GSK3 promoted ROS. Moreover, in both the retina of diabetic mice and in retinal cells exposed to hyperglycemic conditions, the antioxidant N-acetyl-L-cysteine (NAC) prevented an increase in ROS and normalized REDD1 expression and cell death. Diabetic mice receiving NAC also exhibited improved visual function (i.e., contrast sensitivity) as compared to diabetic controls. Overall, the findings provide new insight into the mechanism whereby diabetes-induced hyperglycemia enhances oxidative stress in retina. Specifically, hyperglycemia-induced REDD1 activates a ROS-generating feedback loop that includes Akt and GSK3. Thus, therapeutic approaches targeting REDD1 expression and ROS may be beneficial for preventing diabetes-induced visual dysfunction.
February 2019- RiboSeq paper is published in JBC.
Congrats to Sadie on her first 1st-Author manuscript!
Diabetes promotes the post-translational modification of proteins by O-GlcNAcylation and thereby contributes to diabetic complications. However, the extent to which this modification alters mRNA translation was unknown. Here, using ribosome profiling, we evaluated the effect of enhanced O-GlcNAcylation on retinal gene expression. The principal effect of O-GlcNAcylation on retinal gene expression was observed in ribosome-associated mRNAs (i.e., mRNAs undergoing translation), as <1% of mRNAs exhibited changes in abundance. Remarkably, ~19% of the transcriptome exhibited TMG-induced changes in ribosome occupancy. These findings provide new evidence for a mechanism whereby diabetes-induced O-GlcNAcylation promotes oxidative stress in the retina by altering the selection of mRNAs for translation.
December 2018- GFAT2 and Ceramide papers are published in FASEB and BBA!
Congrats Weiwei!
The role of dyslipidemia in the development of diabetic complications and particularly diabetic retinopathy (DR) remains poorly understood. Weiwei’s research demonstrates that retinas of mice fed a high fat diet (HFD) exhibit markers of inflammation, insulin resistance, and enhanced O-linked glycosylation prior to the onset of hyperglycemia. His studies were the first to demonstrate that diets high in saturated fats promote changes in retinal sphingolipid profiles in association with attenuation of pro-survival Akt phosphorylation and increased retinal cell death. Weiwei also found that HFD promoted glutamine-fructose-6-phosphate amidotransferase 2 (GFAT2) expression, leading to increased hexosamine biosynthetic pathway (HBP) flux and enhanced protein O-GlcNAcylation. GFAT isoforms catalyze the first and rate-determining step in the HBP. Thus, GFAT isoform expression and activity represent a critical regulatory point in committing glucose to the HBP. Unlike GFAT1, GFAT2 is insensitive to feedback inhibition and thus facilitates dramatic variation in protein O-GlcNAcylation in response to increased glucose availability. Overall, therapeutic strategies to restore normal sphingolipid metabolism or prevent aberrant O-GlcNAcylation may represent viable options for treating DR.
June 2018- Three Abstracts presented at the 78th Scientific Sessions of the American Diabetes Association in Orlando, FL
Dai, W., Dierschke, S.K., Toro, A.L., Miller, W.P., and Dennis, M.D. High fat diet/palmitate-induced ER stress promotes protein O-GlcNAcylation in retina and retinal Müller cells.
Dierschke, S.K., Arnold, A.C., Barber, A.J., and Dennis, M.D. Angiotensin-(1-7) attenuates protein O-GlcNAcylation in the retina of mice fed a high fat diet.
Miller, W.P., Toro, A.L., Barber, A.J., and Dennis, M.D. Deletion of the stress response protein REDD1 prevents hyperglycemia-induced reactive oxygen species production and retinal cell death.
January 2018- REDD1 vision paper highlighted in Diabetes!
Congrats William and Chen!
July 2024- Children’s Miracle Network Funds Trainee Research Grant
This $50K award will fund studies to explore the molecular cause of kidney disease in juvenile diabetes.
Congrats Sid!
June 2024- Diabetic Heart Disease Paper Published in IJMS.
This paper identifies signaling pathways that contribute to cardiac function deficits in diabetic mice.
Congrats Shaunaci!
May 2024- BrightFocus Foundation funds Dr. Subramanian’s Postdoctoral Fellowship
This fellowship will explore the role of REDD1 in RPE injury leading to geographic atrophy.
Congrats Sandeep!
April 2024- JDRF funds Innovative Award to study diabetic complications!
New study funded to examine REDD1 allostery in the kidney and retina
March 2024- IOVS publishes NLRP3 paper
New study explores NLRP3 Inflammasome Priming in the Retina of Diabetic Mice
Congrats Chris!
February 2024- Dr. Yerlikaya receives service award.
Esma was honored with The Purpose Award for Senior Students from the Diverse Graduate Student Group (DGSG).
Congrats Esma!
January 2024- NIH funds R21!
National Eye Institute funds new project to explore a role for REDD1 in age-related macular degeneration.
December 2023- ADA funds Dr. Sunilkumar’s Postdoctoral Fellowship to study diabetic kidney disease
More on the Award in Penn State Health News.
Congrats Sid!
November 2023- Esma receives Patrick G. Quinn Award
Esma received the Patrick G. Quinn award for most outstanding post-candidacy doctoral student in the department of Cellular and Molecular Physiology.
Congrats Esma!
July 2023- Research Award received to study immune cells in kidney
Dr. Sunilkumar received the 2023 Finkelstein Memorial Trainee Research Award to examine a role for REDD1-dependent renal immune response in diabetic nephropathy.
Congrats Sid!
June 2023- GSK3 paper published at JBC
Our manuscript entitled “REDD1-dependent GSK3β dephosphorylation promotes NF-κB activation and macrophage infiltration in the retina of diabetic mice” was accepted for publication. Learn more HERE.
Congrats Sid!
April 2023- AJP features Heart Paper as Top Article!
Our manuscript entitled “PERK/ATF4-dependent expression of the stress response protein REDD1 promotes proinflammatory cytokine expression in the heart of obese mice” was highlighted as a trending article by the American Journal of Physiology-Endocrinology and Metabolism.
Congrats Shaunaci!
March 2023- CHS funds two Microgrants!
Penn State College of Medicine Comprehensive Health Studies (CHS) Program awarded the laboratory 2 seed grants to support new pilot studies:
– Siddharth Sunilkumar (PI) received seed funds to study mechanisms of diabetic kidney disease.
– Sandeep Subrahmanian (PI) received funds to explore age-related macular degeneration.
Congrats Sid and Sandeep!
Lab members win Spring 2023 Travel Awards!
Christopher McCurry and Esma Yerlikaya both received the Joseph M. and Eula C. Lawrence Travel Grant from the Retina Research Foundation and the Morgan Travel Award from the Department of Cellular and Molecular Physiology to attend the Association for Research in Vision and Ophthalmology 2023 Annual Conference.
Congrats Chris and Esma!
December 2022- Retinal inflammation paper published in JBC.
This manuscript provides new mechanistic insight into how diabetes promotes retinal inflammation and supports a working model wherein the stress response protein REDD1 acts to sustain activation of canonical NF-kB signaling.
Learn more about this study HERE.
Congrats Sid!
November 2022- Heart paper accepted at AJP-Endo Met.
This study identifies REDD1 as a missing molecular link that connects the development of endoplasmic reticulum stress in the hearts of obese mice with enhanced production of inflammatory cytokines.
Congrats Shaunaci!
October 2022- SYK paper published in IOVS
This research supports TREM2/DAP12 receptor-adaptor complex signaling via spleen tyrosine kinase (SYK) to promote stabilization of the transcription factor HIF-1α and increased angiogenic cytokine production by Müller glia in the retina of diabetic mice.
Learn more about this study HERE.
Congrats Esma!
September 2022- Redox Switch paper accepted at Diabetes
This manuscript reveals redox regulation of REDD1 and demonstrates a role for a REDD1 disulfide switch in development of oxidative stress in diabetic retinopathy.
Congrats Bill!
August 2022- Kidney Paper published in Diabetes
This manuscript demonstrates a role for REDD1-dependent GSK3 activation in the development of diabetes-induced oxidative stress and glomerular injury.
Learn more about this study HERE.
Congrats Sid!
July 2022- NHLBI funds F31!
This pre-doctoral NRSA fellowship is to investigate the hypothesis that REDD1 plays a maladaptive role in the pathogenesis of heart disease by augmenting the development of oxidative stress and inflammation in cardiomyocytes.
Congrats Shaunaci!
June 2022- Dr. Sunilkumar receives “Post-doc of the Year Award” from Penn State College of Medicine Postdoctoral Society.
Congrats Sid!
May 2022- Manuscript featured on cover of Diabetes
Müller glial expression of REDD1 is required for retinal neurodegeneration and visual dysfunction in diabetic mice. 2022 May 1;71(5):1051-1062. doi: 10.2337/db21-0853.
Learn more about this study HERE.
Congrats Bill and Allyson!
Lab Members win Spring 2022 Awards!
Bill received a Biomedical Sciences Graduation Award, Sid received a Departmental Postdoctoral Travel Award, and Shaunaci received a Morgan Travel Award.
Congrats!
December 2021- Dr. Miller graduates from the Biomedical Sciences PhD program and receives Karl H. Beyer Jr. PhD Scholarship.
Congrats Bill!
September 2021- NEI funds R01!
New project funded to explore redox-modification of REDD1 and its impact on oxidative stress and inflammation in diabetic retinopathy.
June 2021- Dr. Sunilkumar receives Children’s Miracle Network Trainee Research Grant
Congrats Sid!
May 2021- Dr. Dennis receives tenure and promotion to Associate Professor.
Congrats Michael!
April 2021- Glucagon Paper published in Cell Signal.
Congrats to Sid!
These studies provide evidence that glucagon elicits biphasic regulation of mTORC1. The unexpected acute activation of mTORC1/2 signaling by glucagon was associated with an increase in cAMP, dependent on EPAC signaling, and occurred concomitant with an increase in Rap1-GTP loading. These observations are consistent with a growing body of evidence that supports an expanded role for GCG action beyond its traditional role during fasting and hypoglycemia as an opposing signal to insulin. It is tempting to speculate that the findings may offer a potential foundation to understanding some of the surprising benefits of glucagon pharmacotherapy in diabetes.
Lab Members win Spring 2021 Awards!
Sid received the ASBMB Postdoctoral Researcher Award and Bill received the Graduate Alumni Society Award. Congrats!
Two New Diabetic Retinopathy Reviews
published Spring 2021.
December 2020- Rbp4 mRNA translation paper published in AJP- Endo Met.
Congrats Jackie!
RBP4 plays a critical role in development of metabolic disease and visual dysfunction, yet relatively little is known about the mechanisms that regulate its production. Herein we provide evidence for translational control of RBP4 synthesis. We demonstrate that activation of the nutrient-sensitive kinase mTORC1 promotes Rbp4 mRNA translation. The findings support the possibility that targeting Rbp4 mRNA translation represents an alternative to current therapeutic interventions that lower serum RBP4 concentration by promoting urinary excretion of the protein.
November 2020- NIH funds Research Supplement.
Congrats Shaunaci!
May 2020- Dr. Dierschke graduates and publishes CD40 paper in JBC.
Congrats to Sadie for finishing up her dissertation research and successfully defending!
May 2020- Nrf2 paper published in JBC.
Congrats Bill!
The transcription factor Nrf2 plays an important role in combating oxidative stress by promoting the expression of an array of antioxidant genes. Both individuals with diabetes and preclinical diabetes models exhibit evidence of a defect in retinal Nrf2 activation. Bill’s findings support an exciting new model wherein hyperglycemia-induced REDD1 blunts the Nrf2 antioxidant response to diabetes by activating GSK3, which in turn, phosphorylates Nrf2 to promote its degradation.
February 2020- Ang1-7 signaling paper published in IOVS.
Congrats Sadie!
The aim of this study was to investigate the impact of the renin-angiotensin system on retinal protein O-GlcNAcylation. Sadie found that in the retina of mice fed a high fat diet, retinal protein O-GlcNAcylation was augmented. However, mice receiving an ACE inhibitor in combination with the high fat diet, did not exhibit the effect. Notably, the beneficial effect of ACE inhibition was mediated by Ang1-7 signaling to inhibit O-GlcNAc Transferase Activity.
April 2020- National Institutes of Health fund F31!
Congrats Bill!
This 3-year pre-doctoral fellowship from the National Eye Institute is designed to investigate the hypothesis that REDD1 inhibits the endogenous antioxidant response to diabetes in retina by suppressing the synthesis and stability of nuclear factor erythroid-2-related factor 2 (Nrf2).
September 2019- National Institutes of Health fund R01!
This 5-year grant from the National Eye Institute is designed to address a fundamental gap in understanding of the molecular events that produce changes in protein expression within Müller glia leading to the loss of retinal homeostasis in diabetes. The project will investigate the impact of diabetes on the selection of mRNAs for translation in genetically identified Müller cells within the intact retina using a novel RiboTag mouse model.
May 2019- Dr. Dennis receives Samuel Hinkle Junior Faculty Research Award.
Congrats Michael!
This award recognizes the work of an Assistant Professor within five years of appointment to Penn State, demonstrating significant growth and impact in research. Dr. Dennis was recognized for his contributions to the field of diabetic retinopathy.
May 2019- William receives Patrick G. Quinn Award
This award recognizes Outstanding Performance by a Post-Comprehensive PhD Candidate in the Department of Cellular and Molecular Physiolgy.
Congrats Bill!
March 2019- Research Highlighted by Oregon Eye Health
May 2019- William passes comprehensive exam and gets paper published in IOVS.
Congrats Bill!
This study was designed to evaluate the role of the stress response protein REDD1 in diabetes-induced retinal pathology. In the retina of diabetic mice, REDD1 expression and reactive oxygen species (ROS) were increased and REDD1 deletion prevented diabetes-induced ROS. In R28 retinal cells in culture, hyperglycemic conditions enhanced REDD1 expression, the mitochondrial membrane potential, and ROS levels. However, similar effects were not observed in retinal cells lacking REDD1. In REDD1-deficient cells, dominant negative Akt or constitutively active GSK3 promoted ROS. Moreover, in both the retina of diabetic mice and in retinal cells exposed to hyperglycemic conditions, the antioxidant N-acetyl-L-cysteine (NAC) prevented an increase in ROS and normalized REDD1 expression and cell death. Diabetic mice receiving NAC also exhibited improved visual function (i.e., contrast sensitivity) as compared to diabetic controls. Overall, the findings provide new insight into the mechanism whereby diabetes-induced hyperglycemia enhances oxidative stress in retina. Specifically, hyperglycemia-induced REDD1 activates a ROS-generating feedback loop that includes Akt and GSK3. Thus, therapeutic approaches targeting REDD1 expression and ROS may be beneficial for preventing diabetes-induced visual dysfunction.
February 2019- RiboSeq paper is published in JBC.
Congrats to Sadie on her first 1st-Author manuscript!
Diabetes promotes the post-translational modification of proteins by O-GlcNAcylation and thereby contributes to diabetic complications. However, the extent to which this modification alters mRNA translation was unknown. Here, using ribosome profiling, we evaluated the effect of enhanced O-GlcNAcylation on retinal gene expression. The principal effect of O-GlcNAcylation on retinal gene expression was observed in ribosome-associated mRNAs (i.e., mRNAs undergoing translation), as <1% of mRNAs exhibited changes in abundance. Remarkably, ~19% of the transcriptome exhibited TMG-induced changes in ribosome occupancy. These findings provide new evidence for a mechanism whereby diabetes-induced O-GlcNAcylation promotes oxidative stress in the retina by altering the selection of mRNAs for translation.
December 2018- GFAT2 and Ceramide papers are published in FASEB and BBA!
Congrats Weiwei!
The role of dyslipidemia in the development of diabetic complications and particularly diabetic retinopathy (DR) remains poorly understood. Weiwei’s research demonstrates that retinas of mice fed a high fat diet (HFD) exhibit markers of inflammation, insulin resistance, and enhanced O-linked glycosylation prior to the onset of hyperglycemia. His studies were the first to demonstrate that diets high in saturated fats promote changes in retinal sphingolipid profiles in association with attenuation of pro-survival Akt phosphorylation and increased retinal cell death. Weiwei also found that HFD promoted glutamine-fructose-6-phosphate amidotransferase 2 (GFAT2) expression, leading to increased hexosamine biosynthetic pathway (HBP) flux and enhanced protein O-GlcNAcylation. GFAT isoforms catalyze the first and rate-determining step in the HBP. Thus, GFAT isoform expression and activity represent a critical regulatory point in committing glucose to the HBP. Unlike GFAT1, GFAT2 is insensitive to feedback inhibition and thus facilitates dramatic variation in protein O-GlcNAcylation in response to increased glucose availability. Overall, therapeutic strategies to restore normal sphingolipid metabolism or prevent aberrant O-GlcNAcylation may represent viable options for treating DR.
June 2018- Three Abstracts presented at the 78th Scientific Sessions of the American Diabetes Association in Orlando, FL
Dai, W., Dierschke, S.K., Toro, A.L., Miller, W.P., and Dennis, M.D. High fat diet/palmitate-induced ER stress promotes protein O-GlcNAcylation in retina and retinal Müller cells.
Dierschke, S.K., Arnold, A.C., Barber, A.J., and Dennis, M.D. Angiotensin-(1-7) attenuates protein O-GlcNAcylation in the retina of mice fed a high fat diet.
Miller, W.P., Toro, A.L., Barber, A.J., and Dennis, M.D. Deletion of the stress response protein REDD1 prevents hyperglycemia-induced reactive oxygen species production and retinal cell death.
January 2018- REDD1 vision paper highlighted in Diabetes!
Congrats William and Chen!