Functional Genomics Unit
The Unit’s activities are primarily focused on three areas of research:
- Genomics of atherosclerosis and cardiovascular diseases;
- Identification of novel molecular biomarkers for cardiovascular diseases;
- Immune-mediated and inflammatory mechanisms that contribute to the formation of atherosclerotic plaques and vascular remodeling.
The group also collaborates with other Monzino research units on studies investigating the genetics and immunology of atherothrombosis.
Atherosclerosis is a complex, chronic inflammatory disease that affects medium- and large-sized arteries and induces alterations in the phenotype of vascular cells. Scientific evidence indicates that many components of the immune system can disrupt the normal physiology of vessel walls and lipid metabolism, thereby contributing to the onset and progression of atherosclerosis. Understanding the role of the cells and gene networks involved in inflammation and immune responses is therefore crucial for elucidating its pathophysiology.
Functional genomics refers to the investigation of functional aspects related to the genome, including the analysis of mutations that cause the loss or alteration of specific functions, the measurement of molecular activities, and the study of dynamic genomic processes such as gene transcription, translation, and their regulation. Modern “omics” technologies (which measure the complete set of components within a given molecular compartment) quantify multiple biological processes and enable an in-depth understanding of molecular functions and interactions. Through these approaches, it is possible to build conceptual models with sufficient predictive power to analyze the relationships among the elements of a biological system in response to genetic and/or environmental perturbations.
In the case of common cardiovascular diseases, which are multifactorial disorders arising from the interaction of numerous genes together with modifier genes and/or environmental factors, several studies have demonstrated that large-scale gene expression profiling can identify disease-associated signatures. These profiles can, in turn, be developed into molecular diagnostic tools.
The ultimate goal of this Unit is to identify molecular markers and pathogenic mechanisms that:
- May serve as potential therapeutic targets for the prevention and treatment of atherosclerosis and related diseases;
- May improve cardiovascular risk prediction and support the design of intervention strategies aimed at preventing cardiovascular events.
Selected Projects
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Transcriptional and Epigenetic Biomarkers of Cardiovascular Disease
Considerable efforts are currently being devoted to the identification of reliable and innovative diagnostic and/or prognostic biomarkers, as well as novel therapeutic targets, for cardiovascular diseases. Several studies have demonstrated that genomic “signatures” have the potential to reclassify patients with cardiovascular conditions based on the molecular architecture of the individual patient and to accurately predict the likelihood of future cardiovascular events.
The underlying hypothesis is that the identification of circulating transcriptional signatures (including coding and non-coding messenger RNAs) and/or epigenetic signatures (such as microRNAs) may provide robust and reliable biomarkers for the accurate, non-invasive diagnosis and/or risk stratification of cardiovascular disease. The project also investigates how these gene expression patterns reflect disease extent and severity. In particular, correlations are sought between molecular signatures and the number and type of coronary lesions, as assessed by advanced imaging techniques including computed tomography (CT), coronary angiography, and optical coherence tomography (OCT).
Transcriptomic and epigenomic analyses are performed using next-generation sequencing technologies on nucleic acids isolated from whole blood or specific cellular populations obtained from individuals with different forms of coronary artery disease and/or atherothrombotic disease. The aim is to reclassify patients into phenotype-based categories according to their molecular signatures and to develop risk and/or prognostic scores based on gene expression patterns.
Melanocortin System and Vascular Homeostasis
Colombo Lab
Vascular remodeling is a key pathological process underlying many cardiovascular diseases. Following vascular injury or oxidative stress, a complex interplay among distinct cell populations within the vessel wall leads to endothelial dysfunction and local inflammation. These events, in turn, promote vascular smooth muscle cell proliferation, neointimal thickening, and vessel stenosis. Despite major advances in cardiovascular medicine, effective strategies to restore endothelial function and limit pathological vascular smooth muscle cell proliferation remain limited.
The melanocortin system comprises a network of hormonal and paracrine signaling pathways that includes five G protein-coupled melanocortin receptors, peptide agonists derived from the post-translational processing of proopiomelanocortin (POMC), and endogenous antagonists. This system regulates a broad range of physiological functions, including the control of oxidative stress and inflammation, and plays a fundamental role in maintaining tissue homeostasis.
Growing preclinical evidence suggests that activation of specific melanocortin receptor subtypes may represent a promising therapeutic strategy for the treatment of inflammatory disorders. In this context, our research focuses on understanding how modulation of the melanocortin system can preserve vascular homeostasis and prevent pathological vascular remodeling.
Our ultimate goal is to identify novel therapeutic approaches capable of protecting vascular function, limiting inflammation-driven vascular damage, and reducing the progression of cardiovascular disease by targeting this important neuroendocrine signaling network.
