Molecular Mechanisms of Disease

Miguel Seabra2

Miguel Seabra

Principal Investigator

CV

Location:

CEDOC
Campus Sant'Ana
Pólo de Investigação, NMS, UNL
Rua Câmara Pestana, nº 6
Lab 3.16
1150-082 Lisboa, Portugal

Phone: (+351) 218 803 033
Lab ext: 26013
Fax: (+351) 218 851 920
E-mail: miguel.seabra(at)nms.unl.pt

Brochura_CEDOC_Neuro_Retina_MSeabra_01

 
The main aim of our group is to understand fundamental cellular processes such as membrane traffic and how they contribute to human disease. We use a variety of research approaches, including cell culture, microscopy, molecular biology and mouse models. We aim at developing new molecular tools, testing biomarkers and uncovering new gene and cell-based treatments, in an effort to tackle genetic and chronic diseases.
 

Research Areas

Retinal Degeneration
- Cell and Molecular Biology of the Retinal Pigment Epithelium (RPE)
- Age-Related Macular Degeneration (AMD)
- Gene- and Cell-based therapies focusing on the RPE
- Retinal Neurodegeneration

Skin Pigmentation
- Mechanisms of pigment release by melanocytes
- Mechanisms of pigment uptake and processing by keratinocytes
- Melanocyte/keratinocyte cross-talk

Cancer Biomarkers
- Rab GTPases as novel markers in breast and oral cancer

:: Retinal Degeneration
Retinal degeneration disorders affect millions of people worldwide and constitute a set of incurable diseases that gradually progress to blindness. Current treatments focus mainly on symptom management, even though there are still large gaps in our knowledge regarding eye homeostasis and respective control mechanisms. The Retinal Pigment Epithelium (RPE) is a highly specialized layer of cells, representing a fundamental component of the visual unit. In many retinal disorders, photoreceptor degeneration occurs as a consequence of RPE dysfunction. Our group combines expertise in retinal cell biology, both in normal and pathological conditions. For the latter, we have focused our studies on Choroideremia, an X-linked form of retinal degeneration. We are now extending our studies to dissect the role of the RPE in AMD. Furthermore, we are using differentiation methods to derive RPE from human ES and iPS cells. Our RPE in vitro system will be used for fundamental studies as well as for potential translational applications to treat retinal degeneration.
Diabetic retinopathy is a complication of diabetes and a leading cause of vision loss in the working age population worldwide. There are no effective treatments for preventing DR onset or progression to severe late stages. Our goal is to develop new genetic and pharmacological therapeutic strategies to overcome syn loss of function and gain of toxic function, taking advantage of the privileged status of the eye for both therapies. We will also aim to identify new biomarkers for the different DR disease stages and severity degrees.

:: Skin Pigmentation
Regulation of skin pigmentation relies on an intricate crosstalk between the pigment-producing cells – melanocytes – and pigment-recipient cells – keratinocytes. The specific molecular mechanisms, which induce melanocytes to produce and transfer pigment to keratinocytes are mostly unknown. Our group aims at decoding the dialogue between these two skin cell types so as to understand the molecular basis for baseline pigmentation and pigmentation disorders.

:: Cancer Biomarkers
Our work is based on a collaborative study with several Hospitals in the Lisbon area. We focus on developing novel early diagnostic tools and evaluation of disease progression for oral and breast cancer. Oral cancer has high incidence and prevalence rates, even though the oral cavity can be easily observed. Early diagnostic methods are crucial, in order to decrease morbidity and mortality associated to this disease. On the other hand, breast cancer is one of the most prevalent cancers worldwide. Since Rab GTPases have been implicated in multiple cancers, our group focuses mainly on Rab25 and Rab27 as potential biomarkers of disease progression in these types of cancer.

molecular1
 

- "Mechanisms of Cell Death in Choroideremia"
2018-2019
Choroideremia Research Foundation, USA
PI: Miguel C. Seabra
Abstract: Choroideremia (CHM), is an X-linked recessive chorioretinal degeneration disease caused by functional defects in CHM/REP1, a chaperone protein for Rab GTPases, which are critical regulators of multiple steps in membrane traffic pathways. Retinal gene therapy with an adeno-associated viral vector encoding REP1 in patients with CHM is a very promising approach towards a cure. Nevertheless, it remains important to unravel alternative approaches. Here, we propose to study the mechanisms of cell death in CHM with an initial focus on the retinal pigment epithelium (RPE). We propose to dissect the molecular and cellular mechanisms of RPE cell death using a cellular model of CHM RPE based on iPS technology. We expect that the knowledge obtained from this project leads to the development of new therapeutic approaches towards CHM.

- “Lysosome dysfunction in age-related diseases
2018- 2021
Project 30385 (IC&DT – AAC n.º 02/SAICT/2017)
PI: Miguel C. Seabra
Abstract: We hypothesise that dysfunction of the lysosomal network is a critical component in the pathogenesis of age-related macular degeneration (AMD), the most common blinding disease in the western world. We further hypothesise that lysosomal dysfunction is a common and early contributing factor for the onset of other prevalent age-related diseases. The main goal of this project is to establish a molecular signature of dysfunctional lysosomes and study whether there is an imbalance between dysfunctional and normal lysosomes in AMD as well as in ageing and in neurodegenerative diseases. If so, this project will contribute novel biomarkers for AMD and other age-related diseases and pave the way to novel therapeutic approaches. We will also test the hypothesis that lysosomal dysfunction can induce other cellular dysfunctions, such as proteostasis defects, redox imbalance, mitochondrial dysfunction and inflammatory signalling, thereby establishing causal relationships in the pathogenesis of AMD.

- "Recovering neuronal function and promoting neuroprotection in diabetic retinopathy
2018- 2021
Project 29656 (IC&DT – AAC n.º 02/SAICT/2017)
PI: Sandra Tenreiro
Abstract: Diabetic retinopathy is a complication of diabetes and a leading cause of vision loss in the working age population worldwide. There are no effective treatments for preventing DR onset or progression to severe late stages.
We propose that synucleins contribute to retinal degeneration in a similar mechanism to what is known to occur in Parkinson’s disease. Our goal is to develop new genetic and pharmacological therapeutic strategies to overcome synucleins loss of function and gain of toxic function, taking advantage of the privileged status of the eye for both therapies. We will also identify new biomarkers for the different DR disease stages and severity degrees.
This study will provide novel insights to innovative therapies for Diabetic retinopathy targeting early stages of the disease which involves retinal dysfunction and neurodegeneration. Also, biomarkers identification is fundamental to refine personalized medicine and to Diabetic retinopathy patient’s stratification. The emerging results will pave the way for translational research with patients.

- "Biomembrane: Bioengineered in vitro model of retinal pigmented epithelium of human eye"
2017-2020
M-ERA.NET 2/0005/2016 funded by FP7 EU programme
PI: Prof. Giovanni Vozzi, University of Pisa, Italy
Abstract: Age-Related Macular Degeneration (AMD) is the leading cause of blindness in the elderly worldwide: although it does not cause total blindness, there is a progressive loss of high-acuity vision attributable to degenerative and neovascular changes in the macula. Currently, there is neither a cure nor a strategy to prevent AMD. New discoveries, however, are beginning to provide a much clearer picture of the relevant cellular events and biochemical processes associated with early AMD and the ageing process in general. The emerging picture is one where one layer of the retina, the retinal pigmented epithelium appears to be the critical layer responsible for the disease initiation and progression. RPE dysfunction and eventually death lead to pathological changes in the interface with the vascular layer, the choroid, which are typical of AMD.
The main objective of this project is the design and fabrication of an alternative and smart in vitro model to boost the discovery of new therapeutic strategies for age-related macular degeneration. The development of an in vitro model of retinal pigmented epithelium (RPE) interfaced to choroidal vascular network (CVN) is expected to provide a more reliable device for the pharmaceutical testing and the evaluation of custom therapies for each patient. This device, developed during the project, will have an important impact on health care costs as the new materials and the related in vitro models are expected to be more economic than the current testing system.
To reach the goal, a micro- and nano-fabrication techniques will be combined to mimic the physiological role played by the Bruch’s membrane (BrM), the interface between CVN and RPE
This project is integrated in a European consortium of 5 partners, 2 of them are biopharma companies and is funded by FP7 EU programme.

- “Molecular mechanisms of melanosome transfer and processing by keratinocytes"
01/01/2011 –31/12/2013
Fundação para a Ciência e Tecnologia
PI: Miguel C. Seabra

- “Molecular dissection of the intracellular route of Plasmodium in macrophages and dendritic cells
01/10/2010 – 30/09/2013
Fundação para a Ciência e Tecnologia
PI: Miguel C. Seabra

- “Subversion of the host endocytic pathway by Plasmodium sporozoites
01/02/2010 – 31/01/2013
Fundação para a Ciência e Tecnologia
PI: Miguel C. Seabra

- “Functional genomics studies of phagocytosis in retinal pigment epithelium
01/02/2010 – 31/01/2013
Fundação para a Ciência e Tecnologia
PI: Miguel C. Seabra

- “Regulation of retinal growth factors secretion by Rab GTPases"
01/01/2010 – 31/12/2012
Fundação para a Ciência e Tecnologia
PI: Miguel C. Seabra

- “Expression of Rab GTPases in Breast Cancer
01/07/2010 – 30/06/2012
Bolsa Terry Fox / Liga Portuguesa contra o Cancro
PI: Miguel C. Seabra

- “Molecular mechanisms of organelle motility
01/01/2008 – 31/12/2010
Fundação para a Ciência e Tecnologia
PI: Miguel C. Seabra

- “Molecular mechanisms of parasitophorous vacuole formation in malaria infection
01/10/2007 – 31/03/2010
Fundação para a Ciência e Tecnologia
PI: Miguel C. Seabra

  • Hendrix A, Maynard D, Pauwels P, Braems G, Denys H, Van den Broecke R, Belle SV, Cocquyt V, Gespach C, Bracke M, Seabra MC, Gahl WA, Wever OD, Westbroek W. The secretory small GTPase RAB27B regulates invasive tumor growth and metastasis through extracellular HSP90. J. Nat. Canc. Inst., in press (IF: 14.933)
  • Ostrowski M, Carmo NB, Krumeich S, Fanget I, Raposo G, Savina A, Moita CF, Schauer K, Hume AN, Freitas RP, Goud B, Benaroch P, Hacohen N, Fukuda M, Desnos C, Seabra MC, Darchen F, Amigorena S, Moita LF, Thery C. Rab27a and Rab27b control different steps of the exosome secretion pathway. Nature Cell Biol., 2010 Jan;12(1):19-30; sup pp 1-13. (IF: 17.776)
  • Figueiredo AC, Wasmeier C, Tarafder AK, Ramalho JS, Baron RA, Seabra MC. Rab3GEP is the non-redundant guanine nucleotide exchange factor for Rab27a in melanocytes. J Biol Chem. 2008 Aug 22;283(34):23209-16. (IF: 5.581)
  • Lopes VS, Ramalho JS, Owen DM, Karl MO, Strauss O, Futter CE, Seabra MC. The ternary Rab27a-Myrip-Myosin VIIa complex regulates melanosome motility in the retinal pigment epithelium. Traffic. 2007 May;8(5):486-99. (IF: 5.709 )
  • Tolmachova T, Abrink M, Futter CE, Authi KS, Seabra MC. Rab27b regulates number and secretion of platelet dense granules. Proc Natl Acad Sci U S A. 2007 Apr 3;104(14):5872-7. (IF: 9.380)

- Clare Futter, Institute of Ophthalmology, UCL, London, UK

- Graça Raposo, Institut Curie, Paris, France

- Giovanni Vozzi, Università di Pisa – Centro di Ricerca “E. Piaggio”, Pisa, Italy

- Wojciech Swieszkowski, Warsaw University of Technology, Warsaw, Poland

- Eugene Smit, SNC Fibers, South Africa

- Miguel Veja, Allinky Biopharma, Spain

- Davida Gamm, Un. Wisconsin, Madison, USA

 
 

MMD_Lab_2

MMD_team

Miguel Seabra Group2