Our long term goal is to uncover regulatory mechanisms of membrane trafficking and their role in human disease.
For this, we use state-of-the-art techniques, such as live-cell imaging and super-resolution confocal microscopy and a broad range of molecular biology, biochemistry and cell biology methods to advance the knowledge in this area.
We focus on the study of small GTPases of the Rab and Arf families of the Ras superfamily, as these are known to be master regulators of all steps of intracellular trafficking. Mutations in several proteins of these families lead to diseases affecting mainly neurons, cilia and lysosome-related organelles, like melanosomes. Moreover, several of these proteins have been implicated in cancer progression.
Thus, the study of the mechanisms of diseases caused by mutations in Rab and Arf proteins, can shed light on the etiology of these diseases and allow a better understanding of the implicated protein functions and also shed light on new therapeutic strategies.
The skin is the largest organ of the human body and provides protection against external aggressions. The outmost layer, the epidermis is composed mainly by two cell types: melanocytes and keratinocytes. Melanocytes synthesize the pigment melanin and localize to the basal layer. Keratinocytes are present in all the layers and are the final recipients of melanin. Melanin protects skin cells against ultraviolet (UV) radiation-induced damage, which can lead to the onset of skin cancer. Melanin synthesis occurs in specialized organelles called melanosomes, which share several features with lysosomes like low pH, the presence of lysosomal membrane proteins and catalytic enzymes and are thus considered lysosome-related organelles. Once fully mature and located at the tips of melanocyte dendrites, melanosomes are transferred to keratinocytes. We found evidence that the predominant model of melanin transfer is coupled exo/endocytosis, where the melanin core is exocytosed by melanocytes in a process dependent on the small GTPase Rab11b and the exocyst tethering complex, and then internalized by keratinocytes. Despite the crucial role of melanin uptake and processing by keratinocytes for skin pigmentation, the pathways involved have not been characterized. Moreover, after melanin is internalized by keratinocytes, little is known about how it accumulates at the supra-nuclear region of keratinocytes to shield the DNA from UV radiation. Therefore, we propose to study how melanin is internalized and processed by keratinocytes.
Our initial characterization suggests that melanin is stored in specialized endocytic compartments within keratinocytes that are not highly acidic or degradative, allowing it to resist degradation for long periods and remain during the process of differentiation towards the superficial layers of the stratified epithelium. This study has the potential to provide entirely new concepts in the field of skin pigmentation. Pigmentation disorders cause a reduction in the quality of life of those affected due to their social impact. Also, with the modern lifestyle, photoprotection has become an important issue. Thus, this work can also lead to the identification of novel key regulators that will become drug targets for the pharma, biotech and cosmetic industries.
Horizonte 2020 da União EuropeiaO LYSOCIL é um projeto Twinning liderado pela NMS|FCM que visa fortalecer a capacidade de I&D em doenças raras (DRs), ajudando a tornar-se um centro de excelência reconhecido nacional e internacionalmente em I&D em DRs. O CEDOC-NMS|FCM estabeleceu uma parceria com duas instituições líderes internacionais, a Universidade de Münster (WWU), uma instituição Alemã com um forte perfil de investigação em medicina básica, clínica e translacional em DRs e o Instituto Telethon de Genética e Medicina (TIGEM), o principal centro de investigação Italiano dedicado a compreender os mecanismos moleculares das DRs. Esta parceria irá potenciar o conhecimento e experiência multidisciplinar e alargar as redes de colaboração para atingir a excelência da investigação dos parceiros envolvidos.
Research carried out by several of our laboratories is supported by the LYSOCIL project and has been published in Traffic magazine.
The final conference of the LYSOCIL project took place on the 8th and 9th of April at the Hotel Vila Galé in Cascais. It featured presentations from the various project partners and collaborators worldwide, including Italy and Germany.
NOVA Medical School will be present at Ciência 2022, the largest meeting of Science and Technology in Portugal, with full representation of its research with its four Research Units and three Associate Laboratories, during for the entire duration of the event at Centro de Congressos de Lisboa.
The research, carried out by Membrane Traffic in Disease laboratory, led by Duarte Barral, is on the cover of the latest issue of Traffic magazine, a scientific journal dedicated to intracellular transport in disease.
The group led by Duarte Barral, Membrane Traffic in Disease lab, describes a new way of regulating melanin, elucidating the transfer of pigment between human skin cells.
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