Despite the major advances in medicine, many diseases remain a challenge for both the individual and society. To improve prevention, diagnosis, prognosis and therapy, we need to understand both how the system functions normally and how this system is subverted in disease. The Molecular and Cellular Mechanisms of Disease (MCMD) thematic strand investigates a range of systems, processes and mechanisms that underlie several clinically and economically important diseases and disorders. As such, several collaborative research projects have been developed as a joint effort between a number of research groups within the CBMR. This effort ensures that these complementary research groups are included within various national and international research efforts.
MCMD main research lines
Cancer is a disease with great individual and societal impact, and a major topic of MCMD research. The regulation of proliferation and dedifferentiation are central to cancer, and several research projects are focused on these processes. The role of overexpressed proteins (e.g., Hes1), the incorrect localization of transcription factors (e.g., FOXO, p53), aberrant cell signalling, deregulation of onco-, and tumor-suppressor proteins, tissue invasion, metastasis, protein-microenvironment interactions, antioxidant protein interactions and signalling, inflammation and chemotherapy resistance. To complement this fundamental research, network-based approaches are also incorporated to identify the cellular pathways that are involved in the interactions between the tumour and surrounding stromal cells. The MCMD also examines the mechanisms underlying cancer susceptibility and to identify new risk factors and gene loci for cancer. Additional CBMR projects examine the role of cis-regulatory transcription variation affecting tumour biology and the response to chemotherapeutic drugs. All of these important areas are aggressively investigated within the MCMD.
Developmental and genetic diseases
The development of the heart is a finely regulated, critical process. When this process is perturbed children are born with congenital heart defects. The MCMD is focused on understanding the regulatory mechanisms that drive cardiac progenitor cell differentiation and how alterations in this process yields cardiac defects. The MCMD has also developed cellular models of lysosomal storage disorders (e.g., Gaucher’s disease) to investigate the enzymes responsible for these diseases and to explore molecular methods to restore normal enzymatic activity. The MCMD is also examining the influence of cholesterol content on cell membrane homeostasis, fluidity and on enzymatic (ATPase) activity, critical to understand the development of cell membrane-based pathologies such as cancer, lysosomal storage disorders and atherosclerosis. The MCMD is also examining diabetic retinopathy and the factors that promote retinal neovascularization, a critical complication associated with diabetes.
Host-pathogen interactions in disease
Pathogenic and non-pathogenic microorganisms play a vital role in human health and disease. Microbes not only cause infectious disease but also have a significant influence on body homeostasis and the organism’s response to other diseases. Within the CBMR, the MCMD research focuses on virulence factors that assist bacterial pathogens to circumnavigate the host defensive barriers. Other studies focus on the characterization and function of the intestinal microbiota in diabetes and autoimmune disorders. The MCMD is also investigating the role of host gene polymorphisms that encode drug metabolizing enzymes and transporters that effect the efficiency and safety of therapeutics directed against pathogens (e.g., Plasmodium [malaria]).
Developmental and neurodegenerative brain disorders
Developmental dyslexia is one of the most common neurodevelopmental disorders with significant consequences for both the individual and society in terms of educational under-achievement, loss of professional opportunity, social-emotional and behavioural problems in adulthood resulting from chronic school failure. Dyslexia shows comorbidity with several other neurodevelopmental disorders (e.g., attention-deficit/hyperactivity disorder, specific language impairment). Current work within the MCMD is focused on the characterization of the cognitive profiles of poor readers in Portugal. The research on implicit learning is in certain respect world leading and the research efforts has recently characterized an association between the FOXP2-regulated gene CNTNAP2, implicit learning and the activity levels in Broca’s region (a classical neocortical language region) measured with fMRI. The CBMR has developed a unique AGL paradigm based on the structural mere-exposure effect in combination with preference/grammaticality classification which we are investigating with eye-tracking, FMRI, and EEG methodology. The role of implicit learning in dyslexia and language development, more generally, is currently a strong research focus and is being conducted with all modern tools available in cognitive neuroscience and functional neuroimaging. Neurodegenerative disorders are a growing problem in the aging populations of modern society. MCMD research is dedicated to the understanding of the molecular mechanisms governing the structure and function of proteins implicated in such disorders. Research is underway within the MCMD to examine the mutated prion protein that, in infected cells, aggregates and triggers neuronal death. Pathway deregulation in neurodegenerative disease is also being investigated through network-based computational analyses. Further MCMD research is dedicated to the clarification of the mechanisms that regulate neural stem cell proliferation and differentiation (neurogenesis) involving brain injury and neuro-inflammation, including epilepsy and stroke.