Unmasking the Perivascular Adipose Tissue's Role in Diabetic Vascular Disease From Molecular Clues to Clinical Impact

Descrizione del progetto

Il grasso nei vasi sanguigni: un nuovo bersaglio per il trattamento del diabete

Il diabete di tipo 2 è uno dei fattori di rischio più significativi per le malattie cardiovascolari, poiché raddoppia la probabilità di sviluppare una malattia coronarica attraverso meccanismi che non sono ancora del tutto chiari. Il tessuto adiposo che circonda i vasi sanguigni si è recentemente rivelato un regolatore attivo della salute vascolare, in quanto rilascia molecole di segnalazione che influenzano la funzione dei vasi sanguigni. Con il sostegno del programma di azioni Marie Skłodowska-Curie, il progetto IMAPERFAT si propone di studiare i cambiamenti molecolari specifici delle cellule nel tessuto adiposo perivascolare nel diabete di tipo 2. Il gruppo di ricerca userà biopsie prelevate da pazienti sottoposti a intervento di bypass per individuare i fattori secreti e determinarne gli effetti sulla funzione vascolare. L’obiettivo è individuare nuovi biomarcatori e bersagli terapeutici per le malattie cardiovascolari associate al diabete.

Obiettivo

Cardiovascular disease (CVD), such as coronary artery disease (CAD), is currently the largest global killer. Despite current therapeutic measures, patients with type 2 diabetes (T2DM) present a two-fold increased risk of developing CAD compared to people without T2DM. This highlights the unmet medical need for more powerful preventive/therapeutic measures for T2DM-linked CAD. One of the emerging anti-T2DM-linked CAD targets is the perivascular adipose tissue (PVAT), which releases various factors to mediate local vascular endothelial function. As endothelial dysfunction, reflected by impaired vasorelaxation, in T2DM is closely linked to the development of CVD, targeting PVAT-vascular endothelium crosstalk may open a new therapeutic window.
In this study (IMAPERFAT), the aim is to determine cell-type-specific molecular changes in PVAT in T2DM, and functionally test their therapeutic potential to prevent/treat T2DM-linked endothelial dysfunction and CVD. Using our newly set up biobank of human internal mammary artery (IMA) and its adjacent PVAT biopsies isolated from patients undergoing coronary artery bypass grafting surgery, with CAD with and without T2DM, three research objectives are set out: (1) To characterise cell-type-specific secretory signatures of IMA-PVAT in T2DM (by single-nucleus RNA-sequencing and integrating transcriptomics with paired proteomics of PVAT-conditioned media) (2) To determine the effect of PVAT-released factors on vascular endothelial function in T2DM; (3) set up a translational T2DM-PVAT spheroid model to target adverse PVAT remodelling.
IMAPERFAT will yield a novel transcriptomic dataset of human IMA-PVAT on a single-cell level resolution and may lead to the discovery of biomarker/therapeutic targets for T2DM-linked PVAT and endothelial dysfunction. It is also a fantastic training opportunity for me to develop my interdisciplinary academic research expertise with clinicians and industry partners in the European Union.