Responsabile: dott.ssa Federica Corallini
TRAIL è una molecola che ha suscitato grande interesse per le sue proprietà antitumorali. Tuttavia, parallelamente al suo ruolo in ambito oncologico, il suo potenziale coinvolgimento nelle malattie cardiovascolari e nel diabete mellito sta destando un sempre crescente interesse. Diversi studi hanno inequivocabilmente dimostrato che TRAIL ha proprietà protettive, anti-infiammatorie ed anti-aterosclerotiche suggerendo un ruolo importante di questa proteina nel sistema vascolare e suggerendo che tale attività potrebbe contrastare la severità del diabete mellito. Partendo da queste osservazioni, il progetto si propone di definire il ruolo di TRAIL come biomarcatore prognostico dell’insorgenza e progressione del diabete e di studiare il potenziale terapeutico di TRAIL per il trattamento di pazienti affetti da diabete, così come dei soggetti affetti da sindrome metabolica e che dunque presentano un alto rischio di sviluppare il diabete.
Diabetes mellitus (DM) has reached epidemic levels worldwide and it is estimated that its incidence will increase by more than 100% within 2030, with a concomitant reduction of the earlier age of onset of the disease before 4 years.
Clinical issues related to the disease are focused not only on glucose metabolism, but also on cardiovascular pathologies, which are the likely cause of morbidity and mortality. Moreover, obesity is rising worldwide, and its association with metabolic abnormalities increases the risk for both type 2 diabetes and cardiovascular diseases. Despite recent advances in medical therapies and devices for these pathologies, the incidence, hospitalization and mortality rates remain high and continue to rise. It follows that there is the mandatory need for the development of new treatment modalities for patients affected by diabetes as well as for those individuals characterized by the cluster of metabolically related risk factors, which also predict a high risk of developing diabetes.
TNF-related apoptosis inducing ligand (TRAIL) is a TNF super-family member extensively studied as anticancer agent. However, a growing interest is rising about TRAIL involvement in the setting of cardiovascular diseases and DM. In this respect, the specific aims of the present project are:
- to define the value of circulating levels of TRAIL as prognostic biomarker of diabetes onset and progression;
- to investigate the therapeutic potential of recombinant TRAIL for the treatment of patients affected by diabetes, as well as for those individuals with metabolically related risk factors, which also predict a high risk of developing diabetes.
For the purpose of the proposed project, we plan:
- to assess the possible prognostic value of TRAIL by investigating the relationship between circulating TRAIL level and the clinical follow-up in paediatric/adult patients affected by diabetes as well as in those individuals characterized by the cluster of metabolically related risk factors;
- to evaluate whether recombinant TRAIL delivery may confer protection and/or ameliorates the metabolic abnormalities and/or the cardiovascular complications by using preclinical models of diabetes.
Summary Preliminary Data
Studies of our research group and of other investigators have unequivocally shown that TRAIL exhibits endothelial protective properties as well as anti-inflammatory and anti-atherosclerotic activity both in vitro and in vivo in animal models, suggesting an important role of this protein in vascular system. Moreover, we have demonstrated that TRAIL is able to promote the migration of Mesenchymal Stem cell (MSC), a cellular subset involved in tissue growth/repair and immunomodulation, making this physiological response an attractive therapeutic tool. Additional studies have suggested that the anti-inflammatory and anti-autoimmunitary activity of endogenous TRAIL might counteract the severity of type 1 DM. In this context, we have recently demonstrated that administration of recombinant TRAIL in an animal model of type 1 DM ameliorates the severity of diabetes, at least in part by preserving the morphology and function of pancreatic islets. Consistently with all these studies, we (and others) have documented that the levels of circulating TRAIL are lower in patients affected by cardiovascular diseases, and in particular in those who are also affected by diabetes. Moreover, follow-up studies have demonstrated that decreased circulating levels of TRAIL represent an important predictor of cardiovascular events, independent of conventional risk markers.
Materials and methods:
Circulating levels of TRAIL will be measured by ELISA in serum samples obtained from adult/paediatric patients, affected by:
- type 1 DM at the onset and in the follow-up; ii) metabolic syndrome associated or not to type 2 DM. Moreover, we will evaluate the circulating levels of TRAIL in relationship with other soluble factors known to have a role in vascular complications (CRP, TNF-a; NTproBNP, specific pro-angiogenetic cytokines, homing factors). Multivariate statistical analyses will be performed to identify correlations between TRAIL levels and relevant clinical parameters.
- Type 2 DM animal model will be settled in C57/BL6 mice by using the dietary method. Mice will be treated with recombinant TRAIL or control saline buffer. In addition, the delivery of TRAIL-expressing viral vector or TRAIL-expressing MSC will be evaluated in the same model. Animals will be monitored and clinical and macroscopic parameters will be evaluated at different time points for a total of 3 months.
Main Expected Results and Impact
The results that will derive from these studies could clarify the potentiality of TRAIL as prognostic and therapeutic agent with protective and/or pro-tissue repair activity for patients affected and/or at high risk of diabetes and associated cardiovascular disease. The potential impact of the expected results is particularly relevant considering that DM has reached epidemic levels and its incidence is expected to increase worldwide.
Significance and Relevance for National Health System (SSN)
Diabetes is associated with a 2-fold increase in mortality, with the majority of deaths attributed to cardiovascular causes. Furthermore, the high incidence and hospitalization/care rates are associated with a poor quality of life and increasing medical/social costs. The evaluation of data obtained from both experimental models and clinical study, as proposed in the present project, might provide additional prognostic indicator.