In Italy, stroke causes 67000 yearly deaths, with survivors often having permanent severe disability. Globally, the diffusion of stroke units, the improvements of treatments and better primary prevention have lowered stroke incidence by 17% and mortality by 36% over the last 30 years. Due to some limitations of the available treatments, including a short therapeutic window and the risk of causing a hemorrhagic event, about 40% of patients cannot receive any cure and improved survival is not matched by improved quality of life.
Our research’s goal is to identify the mechanisms underpinning vascular dysfunctions to offer new therapeutic opportunities to treat acute cerebrovascular diseases.
Brain vascular alterations after stroke: the role of the complement system
Functional and structural alterations of cerebral vasculature underlie brain damage and cognitive decline in acute and chronic brain diseases. The complement system (CS) is an early inflammatory response that protects from pathogens. In the brain, the CS is critical for the development, homeostasis and regeneration of neurons throughout life, and is influenced by phenotypic and genetic factors. After stroke (or other acute pathological conditions), the CS activates in a toxic manner contributing to the expansion of the lesion. Grounding on the original hypothesis that the CS contributes to brain damage through enhanced inflammation and vascular dysfunctions, our lab proposes to identify CS molecular fingerprints of altered brain vasculature. To this end, we use human-derived endothelial cell cultures and experimental in vivo models of ischemic stroke. We envisage to foster innovation in precision medicine, offering markers for the definition of patients at risk for cerebrovascular conditions.
Studies on the inflammatory processes contributing to the instability of the atherosclerotic plaque
Ischemic stroke accounts for 87% of all strokes. A major cause of ischemic stroke is represented by atherosclerotic vulnerable plaques, i.e., fatty deposits on the inner vascular walls that are prone to rupture. If a rupture of the plaque occurs, the risk of thromboembolic complications such as stroke is increased. Common diagnostic tools, like the echocolordoppler, are not able to clearly identify such plaques. In our lab, we aim at identifying new circulating biomarkers able to predict the presence of a vulnerable atherosclerotic plaque. The complement system is an inflammatory process involved in plaque’s morphological evolution. We propose that complement proteins may be circulating biosensors of plaque instability and stroke occurrence. We have identified ficolins, initiators of the complement lectin pathway (LP), as putative biomarkers for vulnerable plaques. We aim at analyzing LP’s proteins and downstream active products and other complement pathway proteins seeking markers with high sensitivity and defining their specific intra-plaque mechanisms of action. Our final goal is to advance prevention of neurologic complications and improve therapy by providing a marker for the early detection of rupture-prone atherosclerotic carotid plaques, bearing a risk for stroke.
Contribution of brain’s resident immune cells to neurological disorders in Wiskott-Aldrich syndrome
The Wiskott-Aldrich syndrome (WAS) is a genetic-based rare disease caused by the deficiency of the WAS protein (WASp), an important regulator of immune cell development. As such, subjects with the syndrome commonly display immunodeficiency and insufficient platelets. Autoimmune diseases due to defective immune cell development and bleeding due to low platelets are typical consequences of WAS during adult life. WAS may cause neurological disorders. The mechanism responsible for neuronal dysfunction has not been clarified in detail; neuronal and non-neuronal cells, like microglia and resident macrophages, might be specifically affected. High levels of WAS are expressed in microglia and tissue macrophages, the resident immune cells in the brain. These cells actively survey the brain, ensuring its normal functions under physiological conditions and get activated in diseases. Moreover, they play important roles during the development of the brain by sculpting neuronal wiring and contributing to cerebrovascular networking. To better clarify the pathogenesis of WAS, our project aims to define: i) if WASp is implicated in pathophysiological functions of microglia/macrophages, and ii) its deficiency causes neurological consequences. We will combine in vitro studies using human-derived neuronal, myeloid and microvascular cell cultures. The neurological consequence of WASp deficiency will be investigated in mouse model of the syndrome.
International Consensus on Cardiopulmonary Resuscitation.