Characterization of the role of gap junction proteins in ER stress and obesity


Principal Investigator: Amir Tirosh
Abstract: DESCRIPTION (provided by applicant): Obesity is a major problem worldwide that increases risk for a wide range of diseases, including diabetes and heart disease. Extensive research in recent years has unraveled many cellular mechanisms in obesity, integrating metabolic signals and inflammatory pathways. Endoplasmic reticulum (ER) stress has been shown to play an important role in metabolic diseases and is linked to both metabolic and immune regulation. While the cellular mechanisms linking overnutrition to ER stress, inflammation and disruption of insulin signal transduction have been extensively studied, the adaptation at the tissue level as a network of living and communicating cells has not been explored. In recent years, it has been shown that gap junction channels play a pivotal role in tissue adaptation to stress and inflammation in various tissues and pathophysiological conditions. Gap junctions facilitate direct cytoplasmic communication between neighboring cells, allowing the transfer of small-molecular-weight molecules involved in cell signaling and metabolism and promoting tissue survival. Assessing the potential role of cell-cell communication through gap junctions in obesity and diabetes in metabolically relevant tissues such as liver and adipose tissue is the primary focus of this proposal. The overarching hypothesis of this project is that obesity-induced ER stress in liver and adipose tissue requires increased gap junction mediated cell-cell communication in order to manage stress and to maintain tissue function and whole-body metabolic homeostasis. Abnormal activation of liver and/or adipose tissue gap junctions may, therefore, represent a novel mechanism for obesity induced metabolic abnormalities. The aim of this study is to assess the potential role of the gap junction proteins (connexins [Cxs]) in the adaptation of liver and adipose tissue to ER stress, overnutrition and obesity. The regulation of connexins under these conditions will be studied, as will their potential to improve tissue dysfunction and whole-body metabolism in obesity and diabetes. A thorough understanding of the plausible role of gap junction communication in maintaining metabolic homeostasis in normal physiology and under conditions of nutrient excess is important to fully understand, and to subsequently treat, chronic metabolic diseases.
Funding Period: 2012-09-15 - 2017-07-31
more information: NIH RePORT

Research Grants

Detail Information

Research Grants30

  1. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013
    ..5) To prepare and empower our diverse Native and Pacific People communities to take ownership of their own health and wellness. ..
  2. Program Project: Growth, Differentiation and Disease of Urothelium
    Tung Tien Sun; Fiscal Year: 2013
    ..abstract_text> ..
  3. Notch and Regulators of Notch Signaling Impact Both Glucose and Lipid Metabolism
    UTPAL BHAGIRATH PAJVANI; Fiscal Year: 2013
    ..Pajvani will need in order to become an independent translational medical researcher and a productive member of the academic medical community. ..
  4. Group X sPLA2: Regulator of lipolysis and glucose homeostasis
    Nancy R Webb; Fiscal Year: 2013
    ..This proposal could provide new strategies to prevent or treat diabetes. ..
  5. Development of iPS Cells for Treatment of Hemoglobinopathies
    Yuet Wai Kan; Fiscal Year: 2013
    ..The science in the Projects will be augmented by an administrative (Core A) and 2 scientific Cores: Core B: Cell and Molecular Biology, and Core C: Cell Transplantation and Analysis. ..
  6. MiR-33 and Aging: Implications for Metabolic Syndrome
    Leigh Goedeke; Fiscal Year: 2013
  7. Pathobiology of the Enteric System
    Joseph H Szurszewski; Fiscal Year: 2013
    ..This highly-integrated Program will make significant progress toward understanding the pathobiology of the enteric system in gastric emptying disorders and translate this knowledge into new diagnostic tools and therapy. ..
  8. Basic and Clinical Studies of Cystic Fibrosis
    Raymond A Frizzell; Fiscal Year: 2013
    ..The Core Center will operate a Pilot and Feasibility Program to bring new investigators into CF research. This Center emphasizes the translation of basic knowledge into applied therapeutics. ..
  9. Macrophage AMPK, Inflammation, and Atherosclerosis
    Bingzhong Xue; Fiscal Year: 2013
    ..Completing these studies will greatly improve our knowledge on the role of macrophage AMPK in the protection against inflammation-associated metabolic disorders, including atherosclerosis and insulin resistance. ..
  10. Lipids, Inflammation and Insulin Action
    Gokhan S Hotamisligil; Fiscal Year: 2013
  11. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
    ..End of Abstract) ..
  12. Neutralizing Antibody &AAV FIX Gene Therapy
    Richard J Samulski; Fiscal Year: 2013
    ..The long-term objective of this PPG is to advance basic understanding of vector-cell-animal model interactions for safe gene delivery. ..
  13. Functional Consequences of Impaired Autophagy in Aging
    ANA M CUERVO; Fiscal Year: 2013
    ..Significance: These studies may ultimately lead to fundamental insights for understanding, treating or preventing the metabolic alterations and declined cognitive and immune function characteristic of elders. ..
    Domenico Accili; Fiscal Year: 2013
    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. ..
  16. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  17. Insulin Signaling and Metabolic Effects through CLK2 Kinase
    Pere Puigserver; Fiscal Year: 2013
  18. Function of the Myo-adipo Axis in Human Obesity and Type 2 Diabetes
    ROBERT ROY HENRY; Fiscal Year: 2013
    ..Results from this project will provide molecular mechanisms for metabolic dysfunction seen in vivo in obesity and T2D and identify possible targets for therapeutic interventions. ..
  19. Metabolic effects of adipose lipogenesis
    Timothy E McGraw; Fiscal Year: 2013
    Sonia M Najjar; Fiscal Year: 2013
    ..This should provide a critical test of the causative effect of hyperinsulinemia on insulin resistance, and identify CEACAM1 as a tractable drug target for the development of medications to combat altered metabolic conditions. ..
  21. Role of Eosinophils in Airway Inflammation and Remodeling
    Nizar N Jarjour; Fiscal Year: 2013
    ..Given the prominence of eosinophilic inflammation in a significant proportion of severe asthma patients, these advances will have direct implications for the patients most affected by this very common illness. ..