Regulation of ER stress-induced cell death

Summary

Principal Investigator: Randal J Kaufman
Abstract: DESCRIPTION (provided by applicant): Diabetes is a disease of world-wide epidemic proportion derived from a failure of beta cells to produce relatively sufficient insulin to maintain euglycemia. Recent studies indicate that nutrient fluctuations and insulin resistance drive beta cells to synthesize insulin beyond their capacity for protein folding and secretion and activates the unfolded protein response (UPR). The UPR is an adaptive signaling pathway to promote cell survival upon accumulation of unfolded protein in the endoplasmic reticulum (ER). A subpathway of the UPR is signaled through activation of the ER kinase PERK and phosphorylation of eukaryotic translation initiation factor 2 on the alpha subunit to transiently attenuate protein synthesis, thereby reducing the biosynthetic burden on the beta cell. Recently, we demonstrated that beta cells selectively require phosphorylation of eIF2a and translation attenuation to preserve cell function. However, unresolved ER dysfunction and chronic activation of UPR subpathways increases expression of the proapoptotic transcription factor CAAT-enhancer binding protein homologous protein (CHOP). Chop deletion in insulin-resistant mice profoundly increases beta cell mass and improves beta cell function to maintain glucose-stimulated insulin secretion and prevent progression of diabetes. The results suggest that inhibition of CHOP may have therapeutic value in treatment of human diabetes to increase the function and/or mass of beta cells. To realize this potential, it is necessary to elucidate how CHOP causes beta cell failure. In pursuit of this goal, we have demonstrated that islets from Chop-/- mice are protected from oxidative stress that occurs upon accumulation of unfolded proteins in the ER. In addition, our preliminary unpublished findings show that CHOP does not significantly bind promoter elements of genes that encode apoptotic functions, but rather binds to promoters of genes that encode functions in protein synthesis. These novel findings inspire the hypothesis that CHOP causes beta cell failure by elevating protein synthesis to cause oxidative stress, and suggest an unprecedented link by which protein misfolding in the ER causes oxidative stress. The findings provide an unprecedented link by which protein synthesis and protein folding in the ER causes oxidative stress. In order to test this hypothesis we propose five specific aims to answer five fundamental questions. Aim 1, How does CHOP expression induce oxidative stress and beta cell failure? We use both genetic and pharmacological approaches to test the hypothesis that eIF2a phosphorylation prevents oxidative stress through control of protein synthesis and that CHOP conversely induces oxidative stress by promoting protein synthesis. Aim 2, What is the relationship between protein folding and oxidative stress? We will evaluate proinsulin folding and processing and mitochondrial function in these studies. Aim 3, How do eIF2a phosphorylation and CHOP expression prevent cell death? We will evaluate the role of ATF4 in cell death and screen for genes that regulate ER stress induced cell death. Aim 4, How do eIF2a phosphorylation and CHOP expression alter gene transcription? mRNA expression profiling and analysis of gene promoters that bind CHOP and ATF4 will identify the transcriptional network regulated by CHOP by eIF2/ATF4/CHOP signaling. Aim 5, Does the PERK/eIF2a/CHOP signaling pathway alter mRNA translation in a quantitative and/or qualitative manner? The impact of eIF2a phosphorylation and CHOP expression on mRNA translational efficiency and AUG initiation codon selection will be measured using a new technique of ribosome profiling. The results from all these studies will provide fundamental insight and needed information toward an understanding of how eIF2a phosphorylation and translational control maintain beta cell function and how CHOP causes beta cell failure and should encourage the development of small molecules to modulate the UPR to preserve beta cell function and mass in human diabetes patients. PUBLIC HEALTH RELEVANCE: Diabetes is a world-wide epidemic characterized by an abnormality in glucose homeostasis that results from a failure of beta cells to produce insulin. Recent studies indicate that regulation of protein synthesis is essential for beta cells to elevate insulin production and for beta cell survival. The proposed studies on protein synthesis will provide vital information that should encourage the development of novel therapeutics to treat diabetes.
Funding Period: 2010-09-01 - 2015-05-31
more information: NIH RePORT

Top Publications

  1. pmc Glycoprotein folding and quality-control mechanisms in protein-folding diseases
    Sean P Ferris
    Department of Biological Chemistry and Medical Scientist Training Program, University of Michigan, Ann Arbor, MI 48109, USA
    Dis Model Mech 7:331-41. 2014
  2. ncbi Targeting endoplasmic reticulum stress in metabolic disease
    Stewart Siyan Cao
    Del E Webb Neuroscience, Aging and Stem Cell Research Center, Sanford Burnham Medical Research Institute, La Jolla, CA 92037, USA
    Expert Opin Ther Targets 17:437-48. 2013
  3. pmc ER stress signalling through eIF2α and CHOP, but not IRE1α, attenuates adipogenesis in mice
    J Han
    Del E Webb Neuroscience, Aging and Stem Cell Research Center, Sanford Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037 1062, USA
    Diabetologia 56:911-24. 2013
  4. pmc IRE1, a double-edged sword in pre-miRNA slicing and cell death
    Justin Hassler
    Del E Webb Neuroscience, Aging and Stem Cell Research Center, Sanford Burnham Medical Research Institute, La Jolla, CA 92037, USA
    Dev Cell 23:921-3. 2012
  5. pmc IRE1α-XBP1s induces PDI expression to increase MTP activity for hepatic VLDL assembly and lipid homeostasis
    Shiyu Wang
    Center for Neuroscience, Aging, and Stem Cell Research, Sanford Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
    Cell Metab 16:473-86. 2012
  6. pmc Thioredoxin-interacting protein mediates ER stress-induced β cell death through initiation of the inflammasome
    Christine M Oslowski
    Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA 01605, USA
    Cell Metab 16:265-73. 2012
  7. pmc The impact of the unfolded protein response on human disease
    Shiyu Wang
    Degenerative Disease Research Program, Neuroscience, Aging, and Stem Cell Research Center, Sanford Burnham Medical Research Institute, La Jolla, CA 92037, USA
    J Cell Biol 197:857-67. 2012
  8. pmc RNA surveillance is required for endoplasmic reticulum homeostasis
    Kenjiro Sakaki
    Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
    Proc Natl Acad Sci U S A 109:8079-84. 2012
  9. pmc Endoplasmic reticulum stress and type 2 diabetes
    Sung Hoon Back
    School of Biological Sciences, University of Ulsan, Ulsan, Republic of Korea
    Annu Rev Biochem 81:767-93. 2012
  10. pmc PKR protects colonic epithelium against colitis through the unfolded protein response and prosurvival signaling
    Stewart Siyan Cao
    Del E Webb Neuroscience, Aging and Stem Cell Research Center, Sanford Burnham Medical Research Institute, La Jolla, California 92037 1062, USA
    Inflamm Bowel Dis 18:1735-42. 2012

Research Grants

Detail Information

Publications44

  1. pmc Glycoprotein folding and quality-control mechanisms in protein-folding diseases
    Sean P Ferris
    Department of Biological Chemistry and Medical Scientist Training Program, University of Michigan, Ann Arbor, MI 48109, USA
    Dis Model Mech 7:331-41. 2014
    ..We describe the GQC pathways and highlight disease and animal models that have been instrumental in clarifying our current understanding of these processes...
  2. ncbi Targeting endoplasmic reticulum stress in metabolic disease
    Stewart Siyan Cao
    Del E Webb Neuroscience, Aging and Stem Cell Research Center, Sanford Burnham Medical Research Institute, La Jolla, CA 92037, USA
    Expert Opin Ther Targets 17:437-48. 2013
    ..Emerging preclinical and clinical evidence supports the notion that pharmacological modulators of ER stress have therapeutic potential as novel treatments of metabolic disorders...
  3. pmc ER stress signalling through eIF2α and CHOP, but not IRE1α, attenuates adipogenesis in mice
    J Han
    Del E Webb Neuroscience, Aging and Stem Cell Research Center, Sanford Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037 1062, USA
    Diabetologia 56:911-24. 2013
    ....
  4. pmc IRE1, a double-edged sword in pre-miRNA slicing and cell death
    Justin Hassler
    Del E Webb Neuroscience, Aging and Stem Cell Research Center, Sanford Burnham Medical Research Institute, La Jolla, CA 92037, USA
    Dev Cell 23:921-3. 2012
    ..Reporting in Science, Upton et al. (2012) broadened our understanding of IRE1α as a cell-death executioner, showing that upon ER stress, IRE1α degrades microRNAs to promote translation of caspase-2...
  5. pmc IRE1α-XBP1s induces PDI expression to increase MTP activity for hepatic VLDL assembly and lipid homeostasis
    Shiyu Wang
    Center for Neuroscience, Aging, and Stem Cell Research, Sanford Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA
    Cell Metab 16:473-86. 2012
    ....
  6. pmc Thioredoxin-interacting protein mediates ER stress-induced β cell death through initiation of the inflammasome
    Christine M Oslowski
    Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, MA 01605, USA
    Cell Metab 16:265-73. 2012
    ..Collectively, our results suggest that TXNIP is a potential therapeutic target for diabetes and ER stress-related human diseases such as Wolfram syndrome...
  7. pmc The impact of the unfolded protein response on human disease
    Shiyu Wang
    Degenerative Disease Research Program, Neuroscience, Aging, and Stem Cell Research Center, Sanford Burnham Medical Research Institute, La Jolla, CA 92037, USA
    J Cell Biol 197:857-67. 2012
    ..Signaling components of the UPR are emerging as potential targets for intervention and treatment of human disease...
  8. pmc RNA surveillance is required for endoplasmic reticulum homeostasis
    Kenjiro Sakaki
    Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
    Proc Natl Acad Sci U S A 109:8079-84. 2012
    ..Importantly, the findings demonstrate a unique and fundamental interaction where NMD-mediated mRNA quality control is required to prevent ER stress...
  9. pmc Endoplasmic reticulum stress and type 2 diabetes
    Sung Hoon Back
    School of Biological Sciences, University of Ulsan, Ulsan, Republic of Korea
    Annu Rev Biochem 81:767-93. 2012
    ..This review examines how the UPR pathways, induced by high glucose and free fatty acids (FFAs), interact to disrupt ER function and cause β-cell dysfunction and death...
  10. pmc PKR protects colonic epithelium against colitis through the unfolded protein response and prosurvival signaling
    Stewart Siyan Cao
    Del E Webb Neuroscience, Aging and Stem Cell Research Center, Sanford Burnham Medical Research Institute, La Jolla, California 92037 1062, USA
    Inflamm Bowel Dis 18:1735-42. 2012
    ..PKR is activated by a number of inflammatory stimuli that are induced in the inflamed intestine. In this study we intended to determine the role of PKR in colonic epithelial cells during experimental colitis in mice...
  11. pmc The unfolded protein response and chemical chaperones reduce protein misfolding and colitis in mice
    Stewart Siyan Cao
    Del E Webb Neuroscience, Aging and Stem Cell Research Center, Sanford Burnham Medical Research Institute, La Jolla, CA 92037, USA
    Gastroenterology 144:989-1000.e6. 2013
    ....
  12. ncbi Neuronal ER stress impedes myeloid-cell-induced vascular regeneration through IRE1α degradation of netrin-1
    François Binet
    Department of Ophthalmology, Maisonneuve Rosemont Hospital Research Centre, University of Montreal, Montreal, QC H1T 2M4, Canada
    Cell Metab 17:353-71. 2013
    ..Degradation of netrin-1, by persistent neuronal ER stress, thereby hinders vascular regeneration. These data identify a neuronal-immune mechanism that directly regulates reparative angiogenesis...
  13. ncbi Phosphorylation of eIF2α is dispensable for differentiation but required at a posttranscriptional level for paneth cell function and intestinal homeostasis in mice
    Stewart S Cao
    Del E Webb Neuroscience, Aging and Stem Cell Research Center, Sanford Burnham Medical Research Institute, La Jolla, California Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, Michigan and Department of Medicine, University of California San Diego, La Jolla, California Dr Cao is now with Columbia University College of Physicians and Surgeons, New York, New York Dr Harrington is now with Medical University of the Americas, Charlestown, Nevis, West Indies
    Inflamm Bowel Dis 20:712-22. 2014
    ..In this study, we examined the mechanistic role of eIF2α-P in intestinal epithelial cell (IEC) function and intestinal homeostasis in mice...
  14. ncbi How does protein misfolding in the endoplasmic reticulum affect lipid metabolism in the liver?
    Shiyu Wang
    Degenerative Disease Research, Center for Neuroscience, Aging, and Stem Cell Research, Sanford Burnham Medical Research Institute, La Jolla, California, USA
    Curr Opin Lipidol 25:125-32. 2014
    ..In this review, we will discuss how altered ER homeostasis contributes to dysregulation of hepatic lipid metabolism and contributes to liver-associated metabolic diseases...
  15. ncbi Measurement of the unfolded protein response to investigate its role in adipogenesis and obesity
    Jaeseok Han
    Center for Neuroscience, Aging, and Stem Cell Research, Sanford Burnham Medical Research Institute, La Jolla, California, USA
    Methods Enzymol 538:135-50. 2014
    ..In this section, we describe how the UPR may contribute to the pathology of obesity, methods to measure UPR induction, and approaches to investigate the role of the UPR during adipocyte differentiation and in mature adipose tissue. ..
  16. pmc eIF2α phosphorylation bypasses premature senescence caused by oxidative stress and pro-oxidant antitumor therapies
    Kamindla Rajesh
    Lady Davis Institute for Medical Research, McGill University, Sir Mortimer B Davis Jewish General Hospital, Montreal, Quebec H3T 1E2, Canada
    Aging (Albany NY) 5:884-901. 2013
    ..Also, inhibition of eIF2αP may be a suitable means to increase the anti-tumor effects of pro-oxidant drugs through the induction of senescence. ..
  17. pmc UDP-glucose:glycoprotein glucosyltransferase (UGGT1) promotes substrate solubility in the endoplasmic reticulum
    Sean P Ferris
    Department of Biological Chemistry and Medical Scientist Training Program, University of Michigan Medical School, Ann Arbor, MI 48109 1621, USA
    Mol Biol Cell 24:2597-608. 2013
    ..These results suggest that UGGT1-dependent monoglucosylation of N-linked glycoproteins promotes substrate solubility in the ER. ..
  18. pmc C/EBP homologous protein-induced macrophage apoptosis protects mice from steatohepatitis
    Harmeet Malhi
    Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, Michigan 48109, USA
    J Biol Chem 288:18624-42. 2013
    ..Thus, macrophage CHOP plays a key role in protecting the liver from steatohepatitis likely by limiting macrophage survival during lipotoxicity. ..
  19. pmc Transcriptional cross talk between orphan nuclear receptor ERRγ and transmembrane transcription factor ATF6α coordinates endoplasmic reticulum stress response
    Jagannath Misra
    Center for Nuclear Receptor Signals, Hormone Research Center, School of Biological Science and Technology, Chonnam National University, Gwangju 500 757, Republic of Korea
    Nucleic Acids Res 41:6960-74. 2013
    ..Overall, for the first time our data show a novel pathway of cross talk between nuclear receptors and ER-membrane-bound transcription factors and suggest a positive feed-forward loop regulates ERRγ and ATF6α gene transcription. ..
  20. pmc A self-defeating anabolic program leads to β-cell apoptosis in endoplasmic reticulum stress-induced diabetes via regulation of amino acid flux
    Dawid Krokowski
    Department of Nutrition, Case Western Reserve University, Cleveland, Ohio 44106, USA
    J Biol Chem 288:17202-13. 2013
    ..These studies suggest that the increased expression of amino acid transporters in islets can serve as early diagnostic biomarkers for the development of diabetes...
  21. pmc ER-stress-induced transcriptional regulation increases protein synthesis leading to cell death
    Jaeseok Han
    Center for Neuroscience, Aging, and Stem Cell Research, Sanford Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, California 92037, USA
    Nat Cell Biol 15:481-90. 2013
    ..The findings suggest that limiting protein synthesis will be therapeutic for diseases caused by protein misfolding in the ER...
  22. pmc Integrated stress response modulates cellular redox state via induction of cystathionine γ-lyase: cross-talk between integrated stress response and thiol metabolism
    Jeffrey G Dickhout
    Department of Medicine, Division of Nephrology, McMaster University, St Joseph s Healthcare Hamilton and Hamilton Centre for Kidney Research, Hamilton, Ontario L8N 4A6, Canada
    J Biol Chem 287:7603-14. 2012
    ..Liver and kidney GSH levels were also reduced in CSE(-/-) mice, suggesting that CSE is a critical factor in GSH synthesis and may act to protect the liver and kidney from a variety of conditions that cause ER stress...
  23. pmc A novel feedback loop regulates the response to endoplasmic reticulum stress via the cooperation of cytoplasmic splicing and mRNA translation
    Mithu Majumder
    Departments of Nutrition, Case Western University School of Medicine, Cleveland, Ohio, USA
    Mol Cell Biol 32:992-1003. 2012
    ..We propose a model in which eIF2α phosphorylation-mediated control of mRNA turnover is a molecular switch that regulates the stress response transcription program and the ER's capacity for protein folding during stress...
  24. pmc In vivo efficacy of platelet-delivered, high specific activity factor VIII variants
    Teshell K Greene
    Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
    Blood 116:6114-22. 2010
    ....
  25. pmc Phosphorylation of eIF2α at serine 51 is an important determinant of cell survival and adaptation to glucose deficiency
    Hala Muaddi
    Lady Davis Institute for Medical Research, Sir Mortimer B Davis Jewish General Hospital, Montreal, QC, H3T 1E2, Canada
    Mol Biol Cell 21:3220-31. 2010
    ..Our data demonstrate that eIF2α phosphorylation is a significant determinant of survival and adaptation of glucose-deficient cells with possible important implications in biological processes that interfere with glucose metabolism...
  26. pmc Domain compatibility in Ire1 kinase is critical for the unfolded protein response
    Juthakorn Poothong
    The Institute of Molecular Biosciences, Mahidol University, Salaya, Nakhon Pathom, Thailand
    FEBS Lett 584:3203-8. 2010
    ..Characterization by domain swapping indicated that a functional ATP/ADP binding domain is minimally required. However the overall domain compatibility is critical for eliciting its full RNase function...
  27. pmc Inositol-requiring 1/X-box-binding protein 1 is a regulatory hub that links endoplasmic reticulum homeostasis with innate immunity and metabolism
    Randal J Kaufman
    Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI, USA
    EMBO Mol Med 2:189-92. 2010
    ..A series of recent studies reveal novel and potentially ancient roles for this pathway in the coordination of metabolic and immune responses...
  28. pmc The role of UDP-Glc:glycoprotein glucosyltransferase 1 in the maturation of an obligate substrate prosaposin
    Bradley R Pearse
    Department of Biochemistry and Molecular Biology, University of Massachusetts, Amherst, MA 01003, USA
    J Cell Biol 189:829-41. 2010
    ..A model is proposed that explains how UGT1 may aid in the folding of sequential domain-containing proteins such as prosaposin...
  29. pmc Protein kinase R contributes to immunity against specific viruses by regulating interferon mRNA integrity
    Oliver Schulz
    Immunobiology Laboratory, Cancer Research UK, London Research Institute, London WC2A 3PX, UK
    Cell Host Microbe 7:354-61. 2010
    ..Our results suggest that PKR plays a nonredundant role in IFN-alpha/beta production in response to some but not all viruses, in part by regulating IFN-alpha/beta mRNA stability...
  30. pmc Temporal regulation of Cat-1 (cationic amino acid transporter-1) gene transcription during endoplasmic reticulum stress
    Charlie C Huang
    Department of Nutrition, School of Medicine, Case Western Reserve University, Cleveland, OH 044106, USA
    Biochem J 429:215-24. 2010
    ..We propose that the signalling via phosphorylated eIF2alpha is required for maximum induction of Cat-1 transcription during the UPR by inducing the accumulation of both ATF4 and XBP1s...
  31. pmc eIF2alpha phosphorylation tips the balance to apoptosis during osmotic stress
    Elena Bevilacqua
    Department of Nutrition, Case Western University School of Medicine, Cleveland, Ohio 44106, USA
    J Biol Chem 285:17098-111. 2010
    ..We propose that eIF2alpha phosphorylation during hypertonic stress promotes apoptosis by sequestration of specific mRNAs in SGs in a process mediated by the cytoplasmic accumulation of hnRNP A1...
  32. pmc A crucial role for RACK1 in the regulation of glucose-stimulated IRE1alpha activation in pancreatic beta cells
    Yifu Qiu
    Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and Graduate School of the Chinese Academy of Sciences, Shanghai 200031, China
    Sci Signal 3:ra7. 2010
    ..Thus, our findings demonstrate that RACK1 functions as a key component in regulating the IRE1alpha signaling pathway in pancreatic beta cells...
  33. pmc The unfolded protein response is required to maintain the integrity of the endoplasmic reticulum, prevent oxidative stress and preserve differentiation in β-cells
    R J Kaufman
    Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, MI, USA
    Diabetes Obes Metab 12:99-107. 2010
    ..The findings suggest an unprecedented link by which protein synthesis and/or misfolding in the ER causes oxidative stress and should encourage the development of novel strategies to treat diabetes...
  34. pmc Endoplasmic reticulum stress in liver disease
    Harmeet Malhi
    Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic, Rochester, MN, USA
    J Hepatol 54:795-809. 2011
    ..Herein we discuss each branch of the UPR and how they may impact hepatocyte function in different pathologic states...
  35. pmc Endoplasmic reticulum-tethered transcription factor cAMP responsive element-binding protein, hepatocyte specific, regulates hepatic lipogenesis, fatty acid oxidation, and lipolysis upon metabolic stress in mice
    Chunbin Zhang
    Center for Molecular Medicine and Genetics, the Wayne State University School of Medicine, Detroit, MI 48201, USA
    Hepatology 55:1070-82. 2012
    ..Supporting the role of CREBH in lipogenesis and lipolysis, forced expression of an activated form of CREBH protein in the liver significantly increases accumulation of hepatic lipids, but reduces plasma TG levels in mice...
  36. pmc Complementary cell-based high-throughput screens identify novel modulators of the unfolded protein response
    Andrew M Fribley
    Carmen and Ann Adams Department of Pediatrics, Division of Hematology Oncology, Wayne State University, 421 E Canfield, Detroit, MI 48201, USA
    J Biomol Screen 16:825-35. 2011
    ..These data support the use of this complementary HTS strategy to identify novel modulators of UPR signaling and tumor cell death...
  37. pmc ER stress and its functional link to mitochondria: role in cell survival and death
    Jyoti D Malhotra
    Department of Biological Chemistry, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA
    Cold Spring Harb Perspect Biol 3:a004424. 2011
    ..We discuss the signaling/communication between the ER and mitochondria and focus on the role of the mitochondrial permeability transition pore in these complex processes...
  38. pmc Eukaryotic initiation factor 2alpha phosphorylation is required for B-cell maturation and function in mice
    Nina Mielke
    Department of Hematology and Oncology, Charite, Campus Virchow Klinikum, University Medicine Berlin, Berlin, Germany
    Haematologica 96:1261-8. 2011
    ..The biochemistry of translation inhibition mediated by eIF2α phosphorylation is well characterized, yet the physiological importance in hematopoiesis remains only partially known...
  39. pmc iRhoms: ERADicating the messenger in growth control signaling
    Stewart Siyan Cao
    Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI 48109, USA
    Dev Cell 20:414-6. 2011
    ..In a recent issue of Cell, Zettl et al. (2011) show that iRhoms regulate growth factor signaling through endoplasmic reticulum-associated protein degradation (ERAD)...
  40. pmc The unfolded protein response transducer IRE1α prevents ER stress-induced hepatic steatosis
    Kezhong Zhang
    Department of Biological Chemistry, University of Michigan Medical Center, Ann Arbor, MI 48108, USA
    EMBO J 30:1357-75. 2011
    ..The identification of IRE1α as a key regulator to prevent hepatic steatosis provides novel insights into ER stress mechanisms in fatty liver diseases associated with toxic liver injuries...
  41. pmc Large-scale analysis of UPR-mediated apoptosis in human cells
    Andrew M Fribley
    Department of Biological Chemistry, University of Michigan School of Medicine, Ann Arbor, Michigan, USA
    Methods Enzymol 491:57-71. 2011
    ....
  42. pmc The unfolded protein response mediates adaptation to exercise in skeletal muscle through a PGC-1α/ATF6α complex
    Jun Wu
    Dana Farber Cancer Institute, Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
    Cell Metab 13:160-9. 2011
    ..These findings suggest that modulation of the UPR through PGC1α represents an alternative avenue to improve skeletal muscle function and achieve metabolic benefits...
  43. pmc Double-stranded RNA-activated protein kinase regulates early innate immune responses during respiratory syncytial virus infection
    Radiah A Corn Minor
    North Carolina A and T University, Greensboro, North Carolina
    J Interferon Cytokine Res 30:263-72. 2010
    ..A genome-wide analysis showed that several early antiviral and immune regulatory genes were affected by PKR activation. These data suggest that PKR is a signaling molecule for immune responses during RSV infections...

Research Grants30

  1. The Shelf Live Evaluation of Investigational Dosage Forms
    Jonathan White; Fiscal Year: 2013
    ..This contract is essential for continued assurance of the quality of drugs undergoing clinical investigation for different types of cancer by Cancer Therapeutics Evaluation Program. ..
  2. Role of Lipid Droplet Proteins in Islet Function in Diabetes and Obesity
    Yumi Imai; Fiscal Year: 2013
    ..Anticipated results will provide better understanding of the regulation of lipid metabolism in islets and will facilitate new approaches towards the prevention and treatment of type 2 diabetes. ..
  3. FASEB SRC: From Unfolded Proteins in the Endoplasmic Reticulum to Disease
    Erik L Snapp; Fiscal Year: 2013
    ....
  4. MPD RESEARCH CONSORTIUM
    Ronald Hoffman; Fiscal Year: 2013
    ..abstract_text> ..
  5. Molecular Regulation of Cell Development and Differentiation
    Dale R Abrahamson; Fiscal Year: 2013
    ..abstract_text> ..
  6. MMC and VICC: Partnership for Survivorship (1 of 2)
    Maureen Sanderson; Fiscal Year: 2013
    ..abstract_text> ..
  7. BARRIER FUNCTION OF THE GI TRACT IN HEALTH AND DISEASE
    W Allan Walker; Fiscal Year: 2013
    ..abstract_text> ..
  8. System Biology Center in New York
    SRINIVAS RAVI V IYENGAR; Fiscal Year: 2013
    ..abstract_text> ..
  9. Regulation of Gene Expression During Stress
    Maria Hatzoglou; Fiscal Year: 2013
    ..Our studies will reveal novel biomarkers in ER stress-induced diabetes (a condition related to T2DM), with diagnostic and therapeutic potential. ..
  10. Synergy of ER stress and oxidative stress after TBI
    Raghu Vemuganti; Fiscal Year: 2013
    ....
  11. Mechanisms of Beta Cell Function in Health and Disease
    CARMELLA EVANS EVANS-MOLINA; Fiscal Year: 2013
    ..The successful completion of these aims will precisely define the role of islet beta cell SERCA2 in metabolic and glucose homeostasis and identify the pathways that lead to its transcriptional dysregulation in Type 2 diabetes mellitus. ..
  12. Program Project: Growth, Differentiation and Disease of Urothelium
    Tung Tien Sun; Fiscal Year: 2013
    ..abstract_text> ..
  13. Role of the Unfolded Protein Response in Beta Cell
    Randal J Kaufman; Fiscal Year: 2013
    ..Is Atfda and/or Atfdp deletion detrimental to p cells upon I r e l d ''deletion, HFD feeding, or Akita mutation? ..
  14. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
    ..End of Abstract) ..
  15. DIABETES AND ENDOCRINOLOGY RESEARCH CENTER
    Domenico Accili; Fiscal Year: 2013
    ....
  16. Interactions Between Inflammation, Oxidant Stress and Cardiovascular Disease
    David G Harrison; Fiscal Year: 2013
    ..Overall, these studies will promote our understanding of the interplay between inflammation, oxidant stress and cardiovascular disease. ..
  17. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
    ..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..
  18. Rescued Secretion of Misfolded Mutant Proinsulin
    JORDAN JAMES WRIGHT; Fiscal Year: 2013
    ..abstract_text> ..
  19. METABOLIC CONTROL OF PROINSULIN BIOSYNTHESIS TRANSLATION
    Christopher J Rhodes; Fiscal Year: 2013
    ..Indeed, in the spirit of translational medicine, the feasibility of such a strategy will also be examined in preclinical models in this proposal. ..
  20. Age-Induced Impairment of Nutrient Signaling Results in Bone Loss
    CARLOS MIGUEL ISALES; Fiscal Year: 2013
    ..Ultimately, we expect the Program Project to identify new therapeutic strategies and develop specific countermeasures for age-associated declines in musculoskeletal function. ..
  21. Transcriptional and Translational Mechanisms Governing Beta Cell Function
    Raghavendra G Mirmira; Fiscal Year: 2013
    ....
  22. Hepatocyte Growth Factor and the Pancreatic Beta Cell
    Adolfo Garcia-Ocana; Fiscal Year: 2013
    ....
  23. mt-Nd2 and Resistance to Autoimmune Diabetes
    Clayton E Mathews; Fiscal Year: 2013
    ..The studies, as proposed, will provide meaningful data on both the early apoptotic signals that result in human beta cell death as well as insights into how ND2a protects human beta cells. ..
  24. Cytoprotection of Beta Cells Through Modulation of Ire1Alpha Function
    Feroz R Papa; Fiscal Year: 2013
    ..Our project goal is to study these switches at the molecular level using interventional approaches. ..
  25. Alcohol abuse and Endoplasmic Reticulum dysfunction in exocrine pancreas
    Aurelia Lugea; Fiscal Year: 2013
    ....
  26. Caloric Restricted Rodent Colony
    RICK MORIN; Fiscal Year: 2013
    ..The purpose of this project is to develop, maintain and distribute a standing colony ofaged, calorically restricted rodents ofdefined strains for use by investigators in studies of aging. ..