T-cell Co-stimulation in Obesity-induced Inflammation and Atherosclerosis

Summary

Principal Investigator: Vince N Montes
Abstract: DESCRIPTION (provided by applicant): Obesity is an underlying risk factor for atherosclerosis and obesity-associated metabolic disorders. Inflammation has been linked as a key to both these processes. We seek to understand the role of T cells, of the adaptive immune system in these inflammatory processes. With respect to atherosclerosis, activated T cells have been found in human atherosclerotic plaques. We plan to evaluate the role of T cell activation in both adipose tissue and arterial wall inflammation by interfering with their activation by inhibiting tw distinct pathways of T cell co-stimulation. T cells are activated in a two-step process, initially involving T cell receptor- antigen recognition, and then activation of the CD80/86-CD28 pathway. Other co-stimulatory pathways that may be synergistic include the CD40-CD40L pathway. T cell activation is highly dependent on the co- stimulatory actions of these pathways. The CD80/86-CD28 pathway can be inhibited by CTLA-4 Ig, or abatacept, an FDA- approved biologic agent. The CD40-CD40L pathway can be inhibited by a neutralizing antibody to CD40 ligand (CD40L). Although blocking the CD40/CD40L pathway with an anti-CD40L antibody has been shown to ameliorate atherosclerosis, the effects of CTLA-4 Ig alone and in conjunction with anti- CD40L antibody on atherosclerosis have not been studied. Since the combination of CTLA-4 Ig and anti- CD40L antibody is a validated method of inducing tolerance in adaptive immune responses, it is important to test this combination in the setting of obesity-associated inflammation and atherosclerosis. The goal of this proposal is to evaluate the effects of these agents alone and in combination in the development of adipose tissue inflammation and atherosclerosis in mice. We plan on using LDL receptor knockout (Ldlr-/-) mice on the C57BL/6 background. These mice are susceptible to adipose tissue inflammation, insulin resistance and atherosclerotic lesion development when placed on a diet that resembles the typical Western diet that is high in saturated fat and cholesterol. In addition, we plan to evaluate the effects of fatty acids and HDL on T cell proliferation in vitro, which can lead to identification of mechanisms of adaptive immune response modulation by these molecules. Also, our preliminary in vitro data suggest a unique property of pre-adipocytes to develop molecules required for professional antigen presentation. We will expand these studies to confirm and identify the significance of this finding. Elucidating important pathways and agents that can mitigate the development of adipose tissue inflammation, insulin resistance and atherosclerosis may lead to further interventions for these conditions in humans. These projects will be part of a structured mentored career development program that will culminate in my becoming an independent investigator as a physician-scientist. My mentor and co- mentors have developed a plan to ensure that I attain my goals within the specified time frame of this opportunity. The research environment at the University of Washington is excellent for a budding physician- scientist, and I plan on taking absolute advantage of the resources available. (End of Abstract)
Funding Period: 2013-08-01 - 2018-05-31
more information: NIH RePORT

Detail Information

Research Grants30

  1. Lipid Homeostasis, Immunity and Atherosclerosis
    Catherine C Hedrick; Fiscal Year: 2013
    ..Regulation of iNKT cell production and activation by ABCG1 is a novel, unexplored role for ABCG1 in immunity that could have profound effects on diseases such as atherosclerosis, rheumatoid arthritis, allergy, and autoimmunity. ..
  2. Optimization of HIV vaccines for the induction of cross-reactive antibodies
    Shan Lu; Fiscal Year: 2013
    ..RELEVANCE: To optimize the next generation polyvalent Env HIV vaccine formulations using the multi-gene, polyvalent DNA prime - protein boost technology platform. ..
  3. Myeloid cell interactions with T cells in atherosclerosis
    Klaus F Ley; Fiscal Year: 2013
    ..PF4 or other molecules investigated here may emerge as targets for prevention or therapy of atherosclerosis and its complications. ..
  4. Discovery and Development of Therapeutic Genes for CHF
    H Kirk Hammond; Fiscal Year: 2013
    ..Four Cores will support the Program: Digital Imaging (Dr. Farquhar);Vector Production (Dr. Miyanohara);Translational Systems (Dr. Hammond) and Clinical &Administrative (Dr. Hammond). ..
  5. Immune Regulation of Virus Clearance and Tissue Injury at Sites of Infection
    Thomas J Braciale; Fiscal Year: 2013
    ..To determine the impact of viral infection on the production of Te-derived IL- 10. The proposed studies are designed to complement ongoing related studies in Projects 2, 3 and 4. ..
  6. 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. ..
  7. Inflammation, Atherosclerosis and ApoA-I
    Mary G Sorci-Thomas; Fiscal Year: 2013
    ..These studies will likely provide new targets for therapeutic interventions to control the inflammatory processes that exacerbate atherosclerosis. ..
  8. Oxidation in Inflammation and Cardiovascular Disease
    Stanley L Hazen; Fiscal Year: 2013
    ..It may also lead to important insights for atherosclerosis risk assessment, diagnosis and therapy. ..
  9. 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. ..
  10. Zimmerman Program for the Molecular and Clinical Biology of VWD
    Robert R Montgomery; Fiscal Year: 2013
    ..Taken together this PPG will set the stage for the appropriate diagnosis and phenotypic understanding of VWD - both in the US and throughout the world. ..
  11. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  12. Regulation of T Cell Responses in Atherosclerosis
    Andrew H Lichtman; Fiscal Year: 2013
    ..Overall, the information obtained will be of direct translational relevance to the development of immunotherapeutic approaches for cardiovascular disease. ..
  13. MOLECULAR BASIS OF CHOLESTEROL METABOLISM
    Joseph L Goldstein; Fiscal Year: 2013
    ..Such an integrated interdisciplinary approach is possible only through continued support of this PPG. ..
  14. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  15. VACCINE INDUCED IMMUNITY IN THE YOUNG AND AGED
    Rafi Ahmed; Fiscal Year: 2013
    ....
  16. Gene Networks controlling macrophage-adipocyte interactions in insulin
    Christopher K Glass; Fiscal Year: 2013
    ..abstract_text> ..
  17. Role of CD40 in Obesity-Induced Adipose Tissue Inflammation &Insulin Resistance
    David L Morris; Fiscal Year: 2013
    ....
  18. 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. ..