The proposal originates within the framework of a collaborative project involving the Interdisciplinary Center of Excellence for the Study of Inflammation (ICSI), and the Section and Operative Unit of Rheumatology. 1.Background. Inflammation has a central role in several diseases, firstly in immuno-mediated rheumatological diseases, burdened by relevant social costs. The current clinical approach for the evaluation of a systemic inflammatory status is based on rather coarse indexes (mainly Erythro Sedimentation Rate and C-reactive protein) , with low specificity and sensitivity, which only allow to obtain a generic information about the underlying biological processes. Therefore, the need to deepen our knowledge of the mechanisms leading to generation of inflammatory mediators and to identify new early and specific markers of inflammation. During the last two years cytokines of the Interleukin-1 family (especially IL-1b and IL-18) have been revaluated for their role in the pathogenesis of inflammatory diseases. Furthermore, the recent identification of the molecular platform (named “inflammasome”) which catalyzes maturation and release of these cytokines in response to exogenous (PAMPs) or endogenous (DAMPs) pro-inflammatory agents , and the dissection of the biochemical pathways involved (P1 and P2 purinergic receptors, pannexins) has offered the opportunity to use early and extremely sensitive markers for monitoring the initial stages of inflammation. A related aspect is the analysis of the effect of product of ATP breakdown on cytokine production and release. 2.This Project aims to use markers of the activation state of the inflammasome as early indicators of inflammation in two immuno-mediated rheumatologic diseases: RA (Rheumatoid Arthritis) and SLE (Systemic Lupus Erythematosus) . Furthermore, we aim to validate these markers as prognostic indicators in the early phases of these diseases. 3.We will investigate the expression pattern of the membrane receptors modulating inflammasome activity (P2 receptors and pannexins), the expression pattern of the individual inflammasome components, and the “in vitro” secretion of IL-1 and IL-18 in peripheral blood leucocytes. In addition, we will measure the blood concentration of extracellular ATP as this nucleotide is the major activator of the inflammasome. The data will be related to the disease, to the standard inflammatory markers, to the disease activity scores and to the other conventional lab parameters. 4.We anticipate to be able to identify early changes in the expression pattern of these markers. This will enable us an early diagnosis of systemic immuno-mediated inflammation and a reliable predictive index.
The inflammasome and its components: new markers for advanced diagnostic in rheumatology.
TROTTA, Francesco
2007
Abstract
The proposal originates within the framework of a collaborative project involving the Interdisciplinary Center of Excellence for the Study of Inflammation (ICSI), and the Section and Operative Unit of Rheumatology. 1.Background. Inflammation has a central role in several diseases, firstly in immuno-mediated rheumatological diseases, burdened by relevant social costs. The current clinical approach for the evaluation of a systemic inflammatory status is based on rather coarse indexes (mainly Erythro Sedimentation Rate and C-reactive protein) , with low specificity and sensitivity, which only allow to obtain a generic information about the underlying biological processes. Therefore, the need to deepen our knowledge of the mechanisms leading to generation of inflammatory mediators and to identify new early and specific markers of inflammation. During the last two years cytokines of the Interleukin-1 family (especially IL-1b and IL-18) have been revaluated for their role in the pathogenesis of inflammatory diseases. Furthermore, the recent identification of the molecular platform (named “inflammasome”) which catalyzes maturation and release of these cytokines in response to exogenous (PAMPs) or endogenous (DAMPs) pro-inflammatory agents , and the dissection of the biochemical pathways involved (P1 and P2 purinergic receptors, pannexins) has offered the opportunity to use early and extremely sensitive markers for monitoring the initial stages of inflammation. A related aspect is the analysis of the effect of product of ATP breakdown on cytokine production and release. 2.This Project aims to use markers of the activation state of the inflammasome as early indicators of inflammation in two immuno-mediated rheumatologic diseases: RA (Rheumatoid Arthritis) and SLE (Systemic Lupus Erythematosus) . Furthermore, we aim to validate these markers as prognostic indicators in the early phases of these diseases. 3.We will investigate the expression pattern of the membrane receptors modulating inflammasome activity (P2 receptors and pannexins), the expression pattern of the individual inflammasome components, and the “in vitro” secretion of IL-1 and IL-18 in peripheral blood leucocytes. In addition, we will measure the blood concentration of extracellular ATP as this nucleotide is the major activator of the inflammasome. The data will be related to the disease, to the standard inflammatory markers, to the disease activity scores and to the other conventional lab parameters. 4.We anticipate to be able to identify early changes in the expression pattern of these markers. This will enable us an early diagnosis of systemic immuno-mediated inflammation and a reliable predictive index.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
