2019 Fellowships Winners

Melanoma is the most aggressive and lethal skin cancer, with highly aggressive behavior and high rate of metastasis. Metastatic melanoma cells migrate from the primary tumor site through lymphatic towards the sentinel lymph node (sLN), where they enter in the blood circulation to invade distant organs, like the lungs or the brain. Despite the importance of the sLN invasion, very few is known about the interaction between immune and cancer cells in this organ. Our preliminary data highlighted the role of subcapsular sinus macrophages (SSM) as the source of IL-1α, a pro-inflammatory cytokine, which is associated to high metastasis formation, while its block is decelerating metastasis growth and spread. Here we propose to characterize, through the use of state-of-the-art techniques like single cell RNA sequencing and intra-vital 2-photon microscopy, the mechanism by which IL-1α promotes tumor spread. In the timeframe of 12 months we aim to understand better the best target to block IL-1α effect and improve currently available immunotherapies.

Similar to brown adipose tissue (BAT), beige fat is a specialized thermogenic form of adipose tissue which is able to convert energy stores into heat by the action of the uncoupling protein 1 (UCP1), or thermogenin. Beige fat mass can be expanded and its activity plays an important role in energy expenditure and substrate utilization. Expansion of beige fat mass and activity is a promising strategy for the treatment of metabolic disorders associated with a sustained positive energy balance, such as obesity and type-2-diabetes. Distinct afferent signals can generate a common “brown” cellular phenotype, but the signal transduction pathways promoting this process are not fully understood. It was discovered that protein tyrosine kinase 2 beta (PTK2B) is highly expressed in beige adipocytes and is critical for beige adipocyte differentiation and thermogenic function. Deletion of PTK2B results in complete inhibition of the beige cellular phenotype. We hypothesize that PTK2B represents a newly discovered critical driver in the process of beige fat differentiation. We propose to characterize, in detail, the role of PTK2B in whole-body metabolism, as an effector of thermogenic adipocyte differentiation. The proposal employs transgenic mouse models to fully characterize the role of PTK2B in the development and trans differentiation of thermogenic fat.

Dietary fiber is digested by gut flora into small molecular metabolites, including short-chain fatty acids (SCFAs) that have many beneficial cardiometabolic properties. We recently demonstrated that oral administration of the SCFA butyrate inhibits appetite and activates brown adipose tissue to burn energy, thereby preventing diet-induced obesity. Through the fecal transplantation and metagenomics studies, we subsequently provided initial evidence of the involvement of a specific gut microbe (termed ‘BugX’, patent-pending) in these beneficial effects of butyrate, although causality should still be demonstrated.

The proposed studies will reveal whether BugX can be applied for the prevention/treatment of metabolic disorders, which may provide valuable information for novel dietary strategies and give leads for product development in the prevention/treatment of metabolic diseases.

Up to 15% of male infertility cases have an immunological origin, due to inflammation or autoimmune responses affecting the epididymis, testis and/or prostate. In this project, we will characterize immunoregulatory mechanisms of the epididymal mucosa, which contributes to the establishment and maintenance of a protective environment that allows the successful maturation and storage of sperm.

Using a multidisciplinary approach, we will contribute to a better understanding of the complex immune system of the epididymis, aiding the prevention of aberrant immune responses against sperm antigens and providing new insights into the mechanisms that modulate immune activation against pathogens in the epididymis. Furthermore, the proposed research has the potential to design new strategies to prevent chronic epididymitis, which currently leads to irreversible infertility, scrotal pain and may reveal novel targets for male contraception.

Clinical diagnosis of Parkinson’s disease (PD) is often achieved when almost half of neurons in substantia nigra are dead. Although, pain-associated PD disease has recently been recognized as a frequent and invalidating symptom, many patients, who complain painful symptoms, are still not considered in the treatment guidelines, leaving their management to the decision of the clinicians alone. Since inflammation and oxidative stress play key roles in neurodegeneration, molecules altered by inflammatory or oxidative processes are expected to be associated with neuronal dysfunction and might represent a powerful tool for evaluating the PD severity in order to prevent its progression towards disabling pain symptoms.

Our scope is to validate oxidative stress biomarkers in the brain for monitoring the severity or progression of the disease. The expected results are also addressed to disclose a new approach in PD-pain associated therapy.