ABSTRACT
The lysosome achieved a new protagonism that highlights its multiple cellular functions, such as in the catabolism of complex substrates, nutrient sensing, and signaling pathways implicated in cell metabolism and growth. Lysosomal storage diseases (LSDs) cause lysosomal accumulation of substrates and deficiency in trafficking of macromolecules. The substrate accumulation can impact one or several pathways which contribute to cell damage. Autophagy impairment and immune response are widely studied, but less attention is paid to morphogenic and growth pathways and its impact on the pathophysiology of LSDs. Hedgehog pathway is affected with abnormal expression and changes in distribution of protein levels, and a reduced number and length of primary cilia. Moreover, growth pathways are identified with delay in reactivation of mTOR that deregulate termination of autophagy and reformation of lysosomes. Insulin resistance caused by changes in lipids rafts has been described in different LSDs. While the genetic and biochemical bases of deficient proteins in LSDs are well understood, the secondary molecular mechanisms that disrupt wider biological processes associated with LSDs are only now becoming clearer. Therefore, we explored how specific signaling pathways can be related to specific LSDs, showing that a system medicine approach could be a valuable tool for the better understanding of LSD pathogenesis. This article is categorized under: Metabolic Diseases > Molecular and Cellular Physiology.
Subject(s)
Biological Phenomena , Lysosomal Storage Diseases , Hedgehog Proteins , Humans , Morphogenesis , Signal TransductionABSTRACT
Los proyectos fisioma están siendo desarrollados por diversa organizaciones y comunidades internacionales. Proponen innovadores enfoques investigativos, formas de organización y utilización de recursos para comprender integralmente, como sistemas, al ser humano y otros eucariotas, desde la concepción hasta la muerte, desde los genes hasta los organismos, a través de multiples escalas de espacio (rango: 10 elevado a 9 en la escala métrica), tiempo (rango: 3 x 10 elevado a 15 en segundos) y organización (moléculas, células, tejidos, organos, organismos). Se pone gran énfasis en el uso de modelos matemáticos/computacionales como herramientas para la integración del conocimiento, la experimentación virtual in sílico, el trabajo colaborativo de numerosos grupos multidisciplinarios internacionales, la creación de grandes bases de datos, ontologías, lenguajes estandarizados, metodologías, infraestructura, repositorios de instrumentos de trabajo; el entrenamiento de nuevos investigadores interdisciplinarios, el desarrollo de organizaciones y comunidades para obtener apoyo financiero, considerar aspectos éticos y legales, validar los modelos, facilitar la aplicación de resultados en la clínica, en la industria, en la enseñanza de los profesionales y en la educación del público, con el fin de maximizar los beneficios sociales. Presentamos el proyecto Fisioma de la Union Internacional de Ciencias Fisiológicas (UICF), y el "Humano Fisiológico Virtual", Eurofisioma, apoyado por la Union Europea. Mencionamos otros proyectos relacionados.
Physiome projects are being developed by several international organizations and communities. They propose innovative approaches to research, organization and resourse allocation aiming to fully understand, as systems, the human being and other eukaryotes, from conception to death, from genes to organisms, through multiple scales of space, time and organization (molecules, cells, tissues, organs, organisms). Great emphasis is placed in the of mathematical/computational modeling, in silico experimentation, international collaborative multidisciplinary work; the creation and share of large data bases, antologies standard languages, methodologies. infrastructures, tools; the training of new interdisciplinary investigators. New organizations are being developed to get funding, to consider ethical and legal aspects, to validate models, to facilitate the application of results from basic research to clinical practice, industry and education of professionals and the general public, in order to maximize social benefits. We will consider the Physiome Projects of the International Union Physiological Sciences (IUPS) and the Virtual Physiological Human (VPH), Europhysiome, supported by the European Union. Other related projects are mentioned.