IMAGING MACROPHAGE ACTIVATION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Summary

Principal Investigator: Delphine L Chen
Abstract: DESCRIPTION (provided by applicant): Chronic obstructive pulmonary disease (COPD) is a prevalent inflammatory lung disease for which new tools to quantify lung inflammation are needed to aid the development of effective anti-inflammatory treatments. Macrophage activation is critical to disease progression, so a technique that can track macrophage recruitment and activation in the lungs would be valuable for delineating inflammatory phenotypes in patients with COPD and for assessing anti-inflammatory treatment responses. Positron emission tomography (PET) is a noninvasive technique that can quantify lung inflammation using [18F]fluorodeoxyglucose ([18F]FDG), a commonly used clinical tracer. The novel PET tracer [11C]PBR28 targets the translocator protein (TSPO), which is present at high levels in activated macrophages. This project will test the overall hypothesis that [11C]PBR28 binding and [18F]FDG uptake measured by PET can be used to differentiate macrophage-dominant inflammation from neutrophil-dominant inflammation in patients with COPD. We will accomplish this by first conducting studies of TSPO expression and glucose uptake in ex vivo mouse models of macrophage activation along with microPET imaging and tissue staining to determine the specificity of [11C]PBR28 and [18F]FDG for macrophages and neutrophils in mice following virus infection- induced chronic obstructive lung disease (Aim 1). We will then study TSPO expression and glucose uptake in polarized human peripheral blood monocytes to parallel the mouse experiments and in lung tissue samples donated at the time of transplant by patients with COPD or at the time of lung resection by healthy donors and patients with milder severity COPD. Finally, we will conduct a small pilot imaging study to obtain preliminary characterization of [11C]PBR28 binding and [18F]FDG uptake in cohorts of individuals with COPD and healthy volunteers as a prelude to a formal clinical trial testing the efficacy of [11C]PBR28 and [18F]FDG in discriminating between macrophage-dominant and neutrophil-dominant inflammation in patients with COPD (Aim 2). PUBLIC HEALTH RELEVANCE: This proposal develops new imaging techniques that can accurately and noninvasively track the activation and recruitment of the different immune cells that contribute to chronic obstructive pulmonary disease (COPD). COPD is a prevalent disease with high morbidity and mortality, but very few effective treatments exist. Investigators will be able to use these new imaging techniques to identify effective anti-inflammatory treatments for COPD more quickly and to better understand how these immune cells contribute to the development of COPD. (End of Abstract)
Funding Period: 2012-09-25 - 2015-06-30
more information: NIH RePORT

Top Publications

  1. pmc Increased T cell glucose uptake reflects acute rejection in lung grafts
    D L Chen
    Division of Radiological Sciences and Nuclear Medicine, Department of Radiology, Washington University School of Medicine, St Louis, MO
    Am J Transplant 13:2540-9. 2013
  2. pmc Synthesis, [¹⁸F] radiolabeling, and evaluation of poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors for in vivo imaging of PARP-1 using positron emission tomography
    Dong Zhou
    Department of Radiology, School of Medicine, Washington University in Saint Louis, St Louis, MO 63110, USA
    Bioorg Med Chem 22:1700-7. 2014

Research Grants

Detail Information

Publications2

  1. pmc Increased T cell glucose uptake reflects acute rejection in lung grafts
    D L Chen
    Division of Radiological Sciences and Nuclear Medicine, Department of Radiology, Washington University School of Medicine, St Louis, MO
    Am J Transplant 13:2540-9. 2013
    ..These data indicate that imaging modalities tailored toward assessing T cell metabolism may be useful in identifying acute rejection in lung recipients...
  2. pmc Synthesis, [¹⁸F] radiolabeling, and evaluation of poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors for in vivo imaging of PARP-1 using positron emission tomography
    Dong Zhou
    Department of Radiology, School of Medicine, Washington University in Saint Louis, St Louis, MO 63110, USA
    Bioorg Med Chem 22:1700-7. 2014
    ..MicroPET studies using [(18)F]12 in MDA-MB-436 tumor-bearing mice demonstrated accumulation of [(18)F]12 in the tumor that was blocked by olaparib, suggesting that the uptake of [(18)F]12 in the tumor is specific to PARP-1 expression...

Research Grants30

  1. Mental Stress Ischemia: Prognosis and Genetic Influences
    Arshed A Quyyumi; Fiscal Year: 2013
    ....
  2. Structure-function based development of JC virion specific antagonists for PML
    Walter Atwood; Fiscal Year: 2013
    ..The three major investigators on the team have built a strong working collaboration that is evidenced by the solid preliminary data supporting this application. ..
  3. Host Factors in Regulation of Inflammatory and Fibroproliferative Lung Disease
    PAUL WESLEY NOBLE; Fiscal Year: 2013
    ..Each of these projects shares the common theme that interactions of host factors regulates inflammatory and fibrotic lung diseases. ..
  4. CENTER FOR BIOMEDICAL RESEARCH
    Timothy Turner; Fiscal Year: 2013
    ..abstract_text> ..
  5. Airway Inflammation and Airway Remodeling
    David H Broide; Fiscal Year: 2013
    ..An lOFM Core is also proposed as requested by the RFA. ..
  6. Genomics for Transplantation: Discovery and Biomarkers
    Daniel R Salomon; Fiscal Year: 2013
    ..Ultimately, we hope to create the genomic tools that will allow physicians to optimize and personalize the safety and efficacy of immunosuppression. ..
  7. B Cells in Health and Disease
    IGNACIO E SANZ; Fiscal Year: 2013
    ..Finally, and central to this PPG, our results will greatly enhance our ability to design better and safer BCDT therapies and to develop biomarkers of B cell targeted treatments efficacy and safety. ..
  8. The University of Texas M. D. Anderson Cancer Center SPORE in Melanoma
    Elizabeth A Grimm; Fiscal Year: 2013
    ..D. Anderson Cancer Center, this SPORE aims to make a significant impact toward the prevention, detection, and treatment of melanoma in patients. ..
  9. SPORE in Genitourinary Cancer
    Colin P N Dinney; Fiscal Year: 2013
    ..Achievement of the aims and objectives of this proposal will result in a major decrease in the incidence, morbidity and mortality of BC. ..
  10. Immune function and the progression to type 1 diabetes
    Mark A Atkinson; Fiscal Year: 2013
    ..In addition, Project 1 holds the promise of providing detailed mechanistic information on disease pathogenesis of human T1D, as well as novel therapeutics for preventing and/or reversing the disorder. ..
  11. Host-pathogen competition in IFN mediated antiviral defense
    Jae U Jung; Fiscal Year: 2013
    ....
  12. VASCULAR RELATIONS OF BLOOD CELLS AND PROTEINS
    Richard E Waugh; Fiscal Year: 2013
    ..The underlying mechanisms for these involve mechanical forces, molecular interactions and cellular properties acting synergistically in ways that are uniquely addressed by this program. ..
  13. Molecular Mechanisms of Arterigenesis
    Michael Simons; Fiscal Year: 2013
    ..matrix (Project 2), evaluate the central role of mTOR in balancing various arteriogenic signaling inputs (Project 3) and determine the role of shear stress and other mechanical factors in initiating arteriogenesis in ad ..
  14. Endothelial Injury and Repair: CardioPulmonary Vascular Biology COBRE
    SHARON IRENE SMITH ROUNDS; Fiscal Year: 2013
    ..abstract_text> ..
  15. Pathophysiology of Alveolar Epithelial Lung Injury
    Jacob I Sznajder; Fiscal Year: 2013
    ..The insights gained from the data generated from these studies will provide novel molecular targets for the development of new therapeutic strategies to treat patients with lung injury. ..
  16. Digitalis-Induced Signaling by Cardiac Na+/K+-ATPase
    Amir Askari; Fiscal Year: 2013
    ..abstract_text> ..
  17. 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. ..
  18. Vascular Subphenotypes of Lung Disease
    Mark T Gladwin; Fiscal Year: 2013
    ..vascular disease Project 3: Pulmonary vascular-targeted NO therapeutic strategies Core A: Administrative core Core B: Pre-Clinical Models of PAH Core C: Translational Vascular Phenomics, Genomics and Epidemiology Core ..
  19. PATHOPHYSIOLOGY OF THE ENDOTHELIUM
    Francis W Luscinskas; Fiscal Year: 2013
    ..g., heart attacks and strokes), as well as other organs and tissues of the body. These mechanistic insights may help identify novel therapeutic targets for the treatment of a broad spectrum of inflammatory diseases. ..
  20. Targeted Modification of Host and Proviral DNA to Treat Latent HIV Infection
    Hans Peter Kiem; Fiscal Year: 2013
    ..Given our leading roles in Transplantation and HIV research, we believe we are uniquely positioned to move these concepts from a highly relevant nonhuman primate HIV/SHIV model toward a cure for HIV-infected patients. ..
  21. ADAPTATIONS TO HYPOXIA
    Kurt R Stenmark; Fiscal Year: 2013
    ..abstract_text> ..