Colorado PROFILES, The Colorado Clinical and Translational Sciences Institute (CCTSI)
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Reversal of Inflammatory Processes in CGD


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Chronic Granulomatous Disease (CGD) is a genetic disease resulting from mutation of the phagocyte NADPH oxidase. While loss of the functioning oxidase results in immunodeficiency, significant disease morbidity is associated with exaggerated, and often sterile, inflammation (e.g. obstructing granuloma, colitis and autoimmunity). Signals downstream of the NADPH oxidase provide necessary control of inflammation, but are poorly understood. Data support that signaling by apoptosing CGD neutrophils and their recognition and engulfment (efferocytosis) by CGD macrophages are defective; these processes ordinarily result in production of anti-inflammatory signals (e.g. TGF?), and are required to resolve inflammation. Specifically, it is hypothesized that absence of reactive oxygen species from the NADPH oxidase results in: i) deficient display of signals on activated and dying CGD neutrophils needed to facilitate macrophage recognition and clearance, and ii) deficient macrophage PPAR? , a master controller of inflammation and macrophage programming for efferocytosis. Inflammatory programming persists in CGD with macrophages unable to clear dying neutrophils, which in turn, accumulate, deteriorate, and fuel exaggerated inflammation and autoimmunity. The specific aims of this investigation are to i) define the normal role of oxidants and PPAR?\? in macrophage programming and their relationship to underlying deficient efferocytosis and over-production of inflammatory mediators in CGD, ii) define the actions of PPAR? agonists in the restoration of CGD macrophage functioning and iii) define the role of oxidants produced by alternative mechanism(s) during PPAR? agonism in reversing the dysfunction of CGD neutrophils and macrophages. This investigation will be carried out in murine and human CGD neutrophils and monocyte/macrophages using sophisticated biochemical, genetic and pharmacological approaches. A well-defined model of granulomatous inflammation in murine CGD will be employed, and together with exploratory endpoints in human CGD phagocytes, will i) elucidate the interconnection between defective ROS production and miscued phagocyte function, and ii) determine whether, and how, restored PPAR? signaling reverses impaired efferocytosis and inflammatory responses. A new hypothesis to explain the persistent inflammatory response in CGD along with its mitigation through PPAR? will support a novel therapeutic approach. This investigation is intended to be a pre-clinical trial of an existing therapy, PPAR? agonists, available for treatment of CGD patients. A thorough understanding of macrophage programming and PPAR? signaling in the recognition and clearance of apoptotic cells in CGD and under normal circumstances is needed. Such findings should also give critical insight into other inflammatory disease states in which macrophage programming and recognition of apoptotic cells appears to be defective.
Collapse sponsor award id
R01AI110408

Collapse Time 
Collapse start date
2014-02-15
Collapse end date
2020-01-31

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