Key words
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Gene silencing; drug delivery; nanovectors; dendrimers; dendrons; DNA/siRNA; molecular modelling; molecular dynamics; HPC computation
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Research programs
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COST-Action TD0802 - Dendrimers in Biomedical Applications
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Short description
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Using molecular modelling techniques, we will provide an essential support to organic chemists in the aim of designing new dendrons molecules devoted to deliver genetic material into cells. Data coming from simulations will give a deep understanding in the energetic and structural aspects of ligand /receptor binding: a promising integration to experiments in the characterization of novel nanocarriers for gene silencing.
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Further information
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Full name of research-institution/enterprise: SUPSI Scuola Universitaria Professionale della Svizzera Italiana Istituto Dalle Molle di studi sull'Intelligenza Artificiale (IDSIA) Università della Svizzera Italiana
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Partners and International Organizations
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B,CZ, DK, FI, FR, DE, IE, IL, IT, LT, NL, NO, PL, RO, ES, SE, CH, TR, UK
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Abstract
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African trypanosomes are protozoan parasites causing African sleeping sickness in humans and nagana in domestic animals. These diseases have a major impact on human and animal health by severely affecting social and economic development among the poorest, mostly rural, populations in sub-Saharan Africa. During its complex life cycle, Trypanosoma brucei alternates between the mammalian bloodstream and the insect host, the tsetse fly. One prerequisite for the parasite to change between the different life cycle forms is its ability to rapidly degrade macromolecules and organelles that are no longer needed in the new environment. This process, which has not been studied in detail in T. brucei, has been suggested to involve autophagy, a mechanism of self-digestion of cellular components that usually occurs without destruction of the cell. Autophagy is an evolutionary conserved mechanism involving approximately 40 gene products in most eukaryotes. Interestingly, due to the apparent lack of several putative autophagy genes in the genome, T. brucei parasites likely possess a machinery consisting of considerably fewer proteins. Atg8, a key protein for autophagy, marks the onset and progression of autophagy in most eukaryotes. In the yeast, Saccharomyces cerevisiae, the role of Atg8 has been well characterized: upon induction of autophagy, Atg8 becomes covalently modified by attachment of the phospholipid, phosphatidylethanolamine, providing Atg8 with a hydrophobic anchor. As a result, the localization of Atg8 changes from the cytosol to the membrane of autophagic vesicles (autophagosomes), where it is involved in membrane expansion and hemifusion. Within the framework of COST action BM0802, we have been studying autophagy in T. brucei by generating several parasite cell lines expressing tagged forms of Atg8 in both procyclic (insect stage) and bloodstream forms. In addition, we have generated knock-out cell lines for two of the key proteins involved in autophagy. We are using these mutant parasites to study the role of autophagy during metabolic starvation and its possible involvement during differentiation of T. brucei.
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References in databases
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Swiss Database: COST-DB of the State Secretariat for Education and Research Hallwylstrasse 4 CH-3003 Berne, Switzerland Tel. +41 31 322 74 82 Swiss Project-Number: C09.0059
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