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Upcoming Seminars

Diego Pasini, Ph.D. - "Control of Cellular Identity by Chromatin Modifying Activities"

Department Experimental Oncology, European Institute of Oncology (IEO), Milan, Italy
When Jan 23, 2018
from 12:00 PM to 01:30 PM
Where Tigem Auditorium "Vesuvius"
Contact Name
Contact Phone 08119230659
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Abstract
Establishing and then maintaining cellular identity during differentiation requires signalling events to be transmitted to the chromatin level; transcription factors (TFs) and chromatin-remodelling activities work together to orchestrate the transcription programs underlying this transmission. It is now clear that chromatin remodelers play a major role in regulating cellular identity, resulting one of the most mutated pathways among all type of human cancers. In this context, Polycomb proteins (PcG) play a crucial role as regulators in development and differentiation and are frequently mutated or altered in their activity in numerous types of human cancers, via molecular mechanisms that are still poorly understood. At the meeting will be presented the recent advances of our laboratory aimed to dissect the molecular mechanisms underling the activity of distinct PcG activities in establishing and maintaining cell type specific transcriptional identity during both normal homeostasis and pathological conditions.


Christian Michael Grimm, M.Sc., Ph.D. - "From mucolipidosis type IV to Ebola: insights into function and pharmacology of endolysosomal cation channels"

Ludwig-Maximilians-Universität (LMU), Department Pharmazie Center for Integrated Protein Science Munich (CIPSM), Munich, Germany
When Jan 29, 2018
from 12:00 PM to 01:30 PM
Where Tigem, Auditorium "Vesuvius"
Contact Name
Contact Phone 081-19230659
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Abstract
My group is interested in the analysis of cation channels of the TRP (transient receptor potential) superfamily within the trafficking network of the endolysosomal system. Lysosomal dysfunction can result in endolysosomal storage disorders (LSDs) such as mucolipidoses or mucopolysaccharidoses but is also implicated in metabolic diseases, the development of neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease, retinal diseases and pigmentation disorders, trace metal deficiencies such as iron deficiency, and even cancer. Highly critical for the proper function of lysosomes, endosomes, and lysosome-related organelles (LROs) is the tight regulation of various fusion and fission processes and the regulation of proton and other cation concentrations within the endolysosomal system (ES). TRPML cation channels (TRPML1, 2 and 3) and Two-pore channels (TPCs) have recently emerged as important regulators of such processes within the ES and appear to be essential for a proper communication between the various endolysosomal vesicles. We use endolysosomal patch-clamp techniques, molecular and cell biology techniques as well as genetic mouse models to study the physiological roles and activation mechanisms of these ion channels in-depth.

Oscar Moran, Ph.D. - "Anion transport mechanisms through lipid bilayers by synthetic ionophores: towards a cystic fibrosis therapy"

Istituto di Biofisica, CNR, Genova, Italy
When Feb 06, 2018
from 12:00 PM to 01:30 PM
Where Tigem, Auditorium "Vesuvius"
Contact Name
Contact Phone 08119230659
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Abstract
Cystic fibrosis (CF) is a genetic lethal disease, originated from the defective function of the CFTR protein, a chloride and bicarbonate permeable transmembrane channel. CF mutations affect CFTR through a variety of molecular mechanisms which result in different functional defects. Current therapeutic approaches are targeted to specific groups of patients that share a common functional defect. We seek to develop an innovative therapeutic approach for the treatment of CF using anionophores, small molecules that facilitate the transmembrane transport of anions. We have characterised the mechanism of anion transport of synthetic molecules based on the structure of  prodigiosine, a red pigment produced by bacteria. Using ion sensitive electrodes (ISE), we measured the chloride eflux from large unilamelar liposomes upon addition of micromolar amounts of anionophores. Data is consistent with a carrier that facilitates the transport of anions  through lipid membranes down the electrochemical gradient. The transport is not coupled with proton or hydroxide translocations. The selectivity sequence of the prodigiosin inspired ionophores is formate > acetate > nitrate > chloride >  bicarbonate. Sulphate, phosphate, aspartate and gluconate are virtually not transported by these anionophores. The transport activity is modulated by the pH at the side where the anionophore is applied, suggesting that the ionization state of the molecule may decide the anion-anionophore interaction. These prodigiosin-derivate ionophores can also induce anion transport in living cells. Their capacity to transport chloride and bicarbonate when applied at low concentration, and  low toxicity take shape as a promising starting point for the development of CF-therapy drug candidates.

The project TAT-CF has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 667079

Angelo Reggiani, Ph.D. - "Glycogen synthase kinase 3β (GSK-3β): More on its role in neuropsychiatric and neurodevelopmental disorders

Department of Drug Discovery, Italian Institute of Technology (IIT), Genova, Italy
When Feb 20, 2018
from 12:00 PM to 01:30 PM
Where tigem, Auditorium "Vesuvius"
Contact Name
Contact Phone 08119230659
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Abstract
Glycogen synthase kinase 3β (GSK-3β) is a serine/threonine protein kinase mediating phosphorylation onto serine and threonine amino acid residues of several target molecules. The enzyme is part of the so called canonical Wnt signaling pathway, is highly conserved across species  and is involved in the regulation of many cellular processes such as cellular proliferation, migration, glucose regulation, and apoptosis. Because of this widespread role aberrant GSK-3β activity has been linked to several disease conditions such as inflammation, neurodegeneration, alteration of circadian clock, neurodevelopmental and psychiatric disorders.
In my talk I will initially focus on how dysregulation of GSK-3β activity can affect mood disorders and I will discuss the potential therapeutic benefit of specific GSK-3 β inhibitors.
Then I will move to discuss the role of GSK-3β in Fragile X syndrome (FXS) also known as Martin-Bell disease, one of the most common genetic causes of autism, due to an expansion of the CGG triplet repeat within the Fragile X mental retardation 1 (FMR1) gene on the X chromosome, resulting in loss of fragile X mental retardation protein (FMRP) expression.
There is now growing evidence of an increased GSK-3β activity in FXS. For example, in FXS animal models a GSK3b overactivation  has been found,  as also confirmed by us in cultured fibroblasts from FXS patients.  Furthermore, we and others have found that in FMR-1 mice the chronic administration of selective inhibitors fully normalizes typical FXS behavioral deficits such as hyperactivity, cognitive disruption and reduced social interaction. Taken together, these findings strongly indicate that GSK3b  is dysregulated in FXS and that  selective inhibitors should ultimately provide benefit to patients. 

Francesco Papaleo, Ph.D. - "A precision medicine genetic marker for core cognitive deficits in schizophrenia"

Genetics of Cognition Laboratory, Department of Neuroscience and Brain Technologies, Italian Institute of Technology (IIT), Genova, Italy
When Feb 27, 2018
from 12:00 PM to 01:30 PM
Where Tigem, Auditorium "Vesuvius"
Contact Name
Contact Phone 08119230659
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Abstract
Antipsychotics are the first-line and most widely used medications for the treatment of schizophrenia spectrum disorders. Clinical responses to these drugs are highly variable. However, predictors of individual responses to antipsychotic treatments have been elusive. Here we report a pharmacogenetics interaction related to a core cognitive dysfunction in patients with schizophrenia. In particular, genetic variations reducing dysbindin-1 expression differentiate individuals with better executive functions responses to antipsychotic drugs. Multilevel ex vivo and in vivo analyses in post mortem human brains, genetically modified mice, andDrosophilae melanogaster demonstrated that such antipsychotics-by-dysbindin-1 interaction is mediated by enhanced presynaptic dopamine D2 function within the prefrontal cortex (PFC). These findings provide a genetic indicator for a biological mechanism underlying cognitive disabilities in patients with schizophrenia, thus paving the way for the implementation of a precision medicine approach to treatment.

Lukas A. Huber, M.D. - "Structure-function relationship of LAMTOR signaling on endosomes"

Biozentrum der Medizinischen Universität Innsbruck, Sektion für Zellbiologie, Innsbruck, Austria
When Mar 06, 2018
from 12:00 PM to 01:30 PM
Where Tigem, Auditorium "Vesuvius"
Contact Name
Contact Phone 08119230659
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Abstract
The LAMTOR [late endosomal and lysosomal adaptor and MAPK (mitogen-activated protein kinase) and mTOR (mechanistic target of rapamycin) activator] complex, also known as "Ragulator," controls the activity of mTOR complex 1 (mTORC1) on the lysosome. The crystal structure of LAMTOR consists of two roadblock/LC7 domain-folded heterodimers wrapped and apparently held together by LAMTOR1, which assembles the complex on lysosomes. In addition, the Rag guanosine triphosphatases (GTPases) associated with the pentamer through their carboxyl-terminal domains, predefining the orientation for interaction with mTORC1. In vitro reconstitution and experiments with site-directed mutagenesis defined the physiological importance of LAMTOR1 in assembling the remaining components to ensure fidelity of mTORC1 signaling. Functional data validated the effect of two short LAMTOR1 amino acid regions in recruitment and stabilization of the Rag GTPases.

Claudio De Virgilio, Ph.D. - "Regulation of TORC1 by Amino Acids: a Central Role for Rag GTPases Within the EGO Complex"

Department of Biology, University of Fribourg, Switzerland
When Apr 03, 2018
from 12:00 PM to 01:00 PM
Where Tigem Auditorium "Vesuvius"
Contact Name
Contact Phone 081-19230659
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Abstract
The eukaryotic target of rapamycin complex 1 (TORC1) couples nutrient, energy, and hormonal signals with cell growth, division, and metabolism, and aberrant TORC1 signaling contributes to the progression of human diseases such as cancer and diabetes. Amino acids are important and primeval cues that stimulate TORC1 to promote anabolic processes (such as ribosome biogenesis and protein translation initiation) and inhibit catabolic processes (such as macroautophagy) via the conserved Rag family GTPases. The latter assemble into heterodimeric complexes consisting of Gtr1 and Gtr2 in yeast, or RagA or RagB and RagC or RagD in mammalian cells. These heterodimers are integral to larger complexes coined EGO (exit from rapamycin-induced growth arrest) complex (EGOC) in yeast or Rag-Ragulator complex in mammalian cells, which are predominantly tethered to vacuolar/lysosomal membranes. Because Rag GTPase heterodimers stimulate TORC1 when they contain GTP-loaded RagA/B/Gtr1 and GDP-loaded RagC/D/Gtr2, GTPase activating proteins (GAPs) acting on Gtr1/RagA/B, such as the orthologous yeast SEACIT or mammalian GATOR1 complexes inhibit, while the ones acting on Gtr2/RagC/D, such as the yeast Lst4-Lst7 or the orthologous mammalian FNIP1/2-Folliculin (FLCN) complexes, activate TORC1. The amino-acid sensitive events upstream of GATOR1 that inhibit TORC1 signaling include the cytosolic leucine and arginine sensors Sestrin2 and CASTOR1, respectively. Both sensors stimulate GATOR1 under amino acid deprivation via a poorly understood mechanism involving their binding to the conserved GATOR1-interacting GATOR2 complex coined SEACAT in yeast. How amino acids activate TORC1 through the Lst4-Lst7/FNIP1/2-FLCN GAP complexes is currently not known. In this context, our current research is focused on deciphering the amino-acid sensitive events upstream of the Rag GTPase regulators in yeast, which likely involve both vacuolar and cytoplasmic amino acid sensors. Due to the evolutionary conservation of the EGOC and its regulators, our studies in yeast are expected to contribute to the understanding of the molecular mechanisms leading to diseases that are associated with hyperactive mammalian TORC1.