Synergy of ER stress and oxidative stress after TBI

Summary

Principal Investigator: Raghu Vemuganti
Abstract: DESCRIPTION (provided by applicant): Efficient functioning of the Endoplasmic reticulum (ER) is indispensable for normal cellular functions as ER plays an important role in the maintenance of intracellular Ca2+ homeostasis, proper folding of proteins, post-translation modifications and transport of nascent proteins to different destinies. Any disruption of ER results in the activation of a complex set of signaling pathways that propagate from the ER to the cytosol to the nucleus. These are collectively known as unfolded protein response (UPR), which is aimed to compensate damage and to restore the normal cellular homeostasis. While limited and transient UPR is beneficial, prolonged or severe UPR, and the ensuing ER stress leads to cell death. Furthermore, CNS insults leads to oxidative stress which is also neurotoxic. We hypothesize that following traumatic brain injury (TBI), ER stress and oxidative stress are coincidental, potentiate each other bi-directionally and synergistically exacerbate the secondary brain damage. Using a rodent model of controlled cortical impact injury, we wish to answer the following questions. (1) What is the role of PERK-mediated ER stress pathway after TBI? (2) In the post-injury brain, are ER stress and oxidative stress connected? In particular, if ER stress mediated by PERK and oxidative stress modulated by NADPH oxidase NOX2 influence each other? (3) What is the effect of knocking-out/inhibiting individual rate-limiting proteins of PERK pathway eif2[unreadable], ATF4 and CHOP on oxidative stress and neuronal damage after TBI? Conversely, what is the effect of knocking-out/inhibiting NOX2 on ER stress and neuronal damage after TBI? The long-term goal is to understand the mutual interplay of ER stress and oxidative stress in post-TBI brain damage.
Funding Period: 2013-07-15 - 2015-06-30
more information: NIH RePORT

Research Grants

Detail Information

Research Grants30

  1. Upper Airway Nerve Injury in Apnea: BIP-CHOP-SIRT1 Crosstalk
    Sigrid C Veasey; Fiscal Year: 2013
    ..The proposed studies are designed to identify novel pathways for therapies to prevent and/or reverse the injuries. ..
  2. 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? ..
  3. Hormonal Signals that Regulate Ovarian Diffrentiation
    Kelly E Mayo; Fiscal Year: 2013
    ..It is our expectation that the basic research projects presented in this P01 program proposal will have considerable impact, ultimately leading to improvements in human reproductive health. ..
  4. The Virtual Physiological Rat Project
    Daniel A Beard; Fiscal Year: 2013
    ..This proposal targets the grand challenge of understanding complex multi-faceted disease phenotypes through experiments and simulations that capture the complex genotype-environment-phenotype relationship. ..
  5. MPD RESEARCH CONSORTIUM
    Ronald Hoffman; Fiscal Year: 2013
    ..abstract_text> ..
  6. Restoration of Endoplasmic Reticulum Function in Experimental Stroke
    Wulf Paschen; Fiscal Year: 2013
    ....
  7. MMC and VICC: Partnership for Survivorship (1 of 2)
    Maureen Sanderson; Fiscal Year: 2013
    ..abstract_text> ..
  8. Center for Excellence in Diabetes and Obesity Research
    ARUNI BHATNAGAR BHATNAGAR; Fiscal Year: 2013
    ..Continued support to the Center will strengthen the infrastructure of biomedical research at the University of Louisville and will positively impact the field of diabete and obesity research worldwide. ..
  9. Mitochondrial Proteins in Parkinson's Disease
    J Timothy Greenamyre; Fiscal Year: 2013
    ....
  10. Attenuating ER and oxidative stress signaling to reduce cell degeneration in vivo
    Feroz R Papa; Fiscal Year: 2013
    ..The elucidation of mechanisms connecting ER and oxidative stress signaling components holds the promise of developing novel drugs to treat diverse cell degenerative diseases, including diabetes. ..
  11. Restoring Mycocardial Healing
    MARK ALAN SUSSMAN; Fiscal Year: 2013
    ..The goal of this program will be to delineate these deleterious signaling mechanisms and determine how they can be overcome to restore endogenous cellular repair processes that heal the damaged heart. ..
  12. ER stress and oligodendrocyte survival after spinal cord injury
    Scott R Whittemore; Fiscal Year: 2013
    ..We expect to identify new acute therapeutic targets that will hopefully extend beyond SCI to other CNS trauma and neurological disease treatment. ..
  13. Metabolic Dysfunction and Neuroprotection after Pediatric Head Injury
    Susanna Scafidi; Fiscal Year: 2013
    ..The studies will also assess whether the natural capability of developing brain to use alternative substrates for energy may provide neuroprotection if these substrates are administered in pharmacologic doses shortly after TBI. ..
  14. 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. ..
  15. Structural bases of the functions of RNA-protein machines
    THOMAS ARTHUR STEITZ; Fiscal Year: 2013
    ..Also of interest will be the ways in which the structures and properties of RNA molecules can be utilized to carry out various biological functions often analogous to those performed by proteins. ..
  16. Rescued Secretion of Misfolded Mutant Proinsulin
    JORDAN JAMES WRIGHT; Fiscal Year: 2013
    ..abstract_text> ..
  17. TBI-Induced Cerebral Metabolic Depression and Recovery
    David A Hovda; Fiscal Year: 2013
    ..This program project will be housed within the UCLA Brain Injury Research Center (Dr. David A. Hovda, Director) so as to assure appropriate imaging, administrative and laboratory support. ..
  18. 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. ..
  19. INTEGRATED MECHANISMS OF CARDIAC MALADAPTATION
    R John Solaro; Fiscal Year: 2013
    ..Studies proposed here offer the potential for novel diagnostic procedures early in the progression of the disorders, and targets for novel therapies. (End of Abstract) ..
  20. Injury and Recovery in Developing Brain
    Flora M Vaccarino; Fiscal Year: 2013
    ..The long-term goal of these studies is to identify new means of therapeutic intervention to decrease the developmental disability and neurobehavioral sequelae of preterm birth. ..
  21. Center for Study of Opioid Receptors and Drugs of Abuse (CSORDA)
    Christopher J Evans; Fiscal Year: 2013
    ..Balleine, Bonci, Koob, Levitt, Nestler and Whybrow ex-officio, will provide programmatic oversight and coordinate training, outreach and a Pilot Program for the center. ..
  22. Alcohol abuse and Endoplasmic Reticulum dysfunction in exocrine pancreas
    Aurelia Lugea; Fiscal Year: 2013
    ....