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Upcoming Seminars

Jean Bennett - "From DNA to FDA: Experiences in Translational Research for Inherited Blindness"

University of Pennsylvania, Philadelphia, USA
When Oct 23, 2017
from 12:00 PM to 01:30 PM
Where Tigem Auditorium "Vesuvius"
Contact Name
Contact Phone 081-19230659
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Abstract
Gene therapy has the potential to reverse disease or prevent further deterioration in patients with incurable degenerative diseases. Studies more than 2 decades in the making, including Phase 1 studies done in collaboration with investigators at TIGEM and Second University of Naples, now nearly 10 years post initiation, showed safe recovery of retinal/visual function in children and adults with congenital blindness due to RPE65 mutations. In a Phase 3 gene therapy trial carried out at The Children’s Hospital of Philadelphia (CHOP) and at the University of Iowa, a total of 29 participants received bilateral injection of the test reagent with nine participants having been randomly assigned to a control group receiving intervention one year later. Eighteen of 20 of the individuals assigned to the early intervention group improved on the primary outcome measure, a multi-luminance mobility maze as shown by read-out of year one measures and 13 passed the test at the lowest light level. None in the untreated comparison group of nine patients improved. Individuals in the control group then received the intervention. They also showed improvement (again with read-out at the year one timepoint). The improvements persisted through the 3 year timepoint (with follow-up ongoing) and there were also improvements in secondary measures. The results answer many questions about the potential benefits and risks of subretinal gene therapy and pave the way for development of additional retinal gene therapy studies. The presentation will include experiences and observations from the Phase 3 studies and speculation about development of retinal gene therapy in the future.

Jolanta Vidugiriene, Ph.D. - "Cellular Metabolism Assays: Revealing the link between metabolic changes and cell function"

Senior Scientist at Promega Corporation
When Oct 23, 2017
from 02:30 PM to 03:30 PM
Where Tigem Auditorium "Vesuvius"
Contact Name
Contact Phone 081-19230659
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Abstract
The growing trend towards understanding the role of cell metabolism in cancer, immunology, obesity, diabetes, and neurodegenerative disease has presented specific challenges in developing rapid and reliable methods for measuring the changes in metabolic pathways. Current technologies are dependent on analytical methods or enzyme-coupled absorbance/fluorescent assays and often require laborious sample preparation and/or lack sensitivity and dynamic range for rapid and convenient metabolite detection directly in 96-well plates.
Here we introduce luminescence metabolite detection assays (e.g. glucose uptake, glucose, lactate, glutamate, NAD(P)/NAD(P)H detection) and discuss how those assays provide valuable information about metabolic reprograming of cancer cells, allow monitoring activation of T cells or evaluation of insulin sensitivity in primary adipocytes.
Changes in metabolic reprograming are often associated with increased ROS levels, and deregulated redox homeostasis is a common feature of cancer cells. We will briefly review the performance of luminescent GSH/GSSG and H2O2 assays and discuss how multiplexing of different assay chemistries and incorporation of normalization readouts, for example viability measurements, into experimental workflow improves data quality and allows you to obtain more information from the same set of samples.  In addition, since metabolic perturbation frequently coincides with alterations in autophagic activity, a reporter-based luminescent assay for microplate determination of autophagic flux will be discussed.

Giovanni D'Angelo, Ph.D. - "Glycosphingolipid Metabolic Reprogramming Drives Neural Differentiation"

Institute of Protein Biochemistry, National Research Council of Italy, Naples
When Oct 31, 2017
from 12:00 PM to 01:30 PM
Where Tigem Auditorium "Vesuvius"
Contact Name
Contact Phone 081-19230659
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Abstract
Neural development is accomplished by differentiation events leading to metabolic reprogramming. Glycosphingolipid metabolism is reprogrammed during neural development with a switch from globo to ganglio-series glycosphingolipids production. Failure to execute the glycosphingolipid switch leads to neurodevelopmental disorders in humans, indicating that glycosphingolipids are key players in this process. Nevertheless, both the molecular mechanisms that control the glycosphingolipid switch and its function in neurodevelopment are poorly understood. Here, we describe a self-contained circuit that controls glycosphingolipid reprogramming and neural differentiation. We find that globo-series glycosphingolipids repress the epigenetic regulator of neuronal genes expression AUTS2. AUTS2 in turn, binds and activates the promoter of the first and rate limiting ganglioside producing enzyme GM3 synthase, thus fostering the synthesis of gangliosides. By this mechanism the globo-AUTS2 axis controls glycosphingolipid reprogramming and neural genes expression during neural differentiation, which involves this circuit in neurodevelopment and its defects in neuropathology.


Paolo Sassone-Corsi, PhD - "Metabolism meets Epigenetics: the Circadian Clock Link"

Center for Epigenetics and Metabolism, School of Medicine, University of California, Irvine - USA
When Nov 07, 2017
from 12:00 PM to 01:30 PM
Where Tigem Auditorium "Vesuvius"
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Contact Phone 081-19230659
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Abstract
The circadian clock is responsible for biological timekeeping on a systemic level. The mammalian central pacemaker is localized in the hypothalamus, in a paired neuronal structure called the suprachiasmatic nucleus (SCN). The discovery that all tissues and virtually all cells contain an intrinsic circadian clock revolutionized the field, providing a conceptual framework towards the understanding of organismal homeostasis and physiological tissue-to-tissue communications. The circadian clock controls a remarkable array of physiological and metabolic functions.
A highly specialized transcriptional machinery based on clock regulatory factors organized in feedback autoregulatory loops governs a significant portion of the genome. These oscillations in gene expression are paralleled by critical events of chromatin remodeling that appear to provide plasticity to circadian regulation. Specifically, various protein acetylation events appear to be under clock control and cycles in both acetyl-CoA and NAD have been linked to circadian control of gene expression. This, and additional accumulating evidence, shows that the circadian epigenome appears to share intimate links with cellular metabolic processes and has remarkable plasticity showing reprogramming during aging and in response to nutritional challenges. As circadian rhythms are intimately linked to aging, and caloric restriction remarkably influences both processes, we have been filling this void in knowledge by revealing the molecular and cellular links between nutrition, metabolism and epigenetic control.

 

 

Antonio Rossi, Ph.D. - "In vivo models of chondrodysplasias caused by defects in proteoglycan biosynthesis: phenotyping and pharmacological approaches"

Department of Molecular Medicine Unit of Biochemistry, University of Pavia, Italy
When Nov 21, 2017
from 12:00 PM to 01:30 PM
Where Tigem Auditorium "Vesuvius"
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Contact Phone 081-19230659
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Abstarct
Heritable skeletal disorders are connective tissue diseases that primarily affect the development and homeostasis of the skeleton; unfortunately, in general no resolutive treatments are available for these painful conditions. Thus, the goal in this research area is the deep phenotyping of relevant in vivo and in vitro models in order to identify and test novel targets for innovative therapies.
In this respect among the skeletal disorders that are being studied in our group, Diastrophic Dysplasia (DTD) and Desbuquois Dysplasia (DBQD) are paradigmatic. Both dysplasias, with similar clinical features, are caused by defects in the biosynthesis of glycosaminoglycan (GAG) chains of proteoglycans (PGs).
DBQD type 1 is caused by mutations in the Calcium-Activated Nucleotidase 1 (CANT1) a Golgi/ER resident enzyme. To define the role of CANT1 in the etiology of DBQD, we generated Cant1 knock-in and knock-out mice. Morphological and clinical observations in the murine strains confirmed the skeletal defects described in the patients. PG synthesis was studied in rib knock-out chondrocytes; mutant cells showed GAG chains with reduced hydrodynamic size, GAG oversulfation, reduced PG synthesis and impaired secretion. This latter observation was confirmed by transmission electron microscopy of mutant vs. wild type cartilage showing the presence of dilated vacuoli suggesting a role of CANT1 in protein secretion.
Nowadays animal models are useful tools to elucidate the molecular mechanisms underlying genetic diseases as described above, but also to develop therapeutic strategies. The dtd mouse is a murine model of Diastrophic Dysplasia (DTD) a skeletal dysplasia caused by mutations in the sulfate-chloride antiporter (SLC26A2), crucial for sulfate uptake and GAG sulfation. Deep phenotyping of the model suggested that N-acetyl-L-cysteine (NAC) might play a role as an intracellular sulfate source for macromolecular sulfation. Because of the important prenatal phase of skeletal development and growth, we administered NAC in the drinking water to pregnant mice to explore a possible transplacental effect on the foetuses. A marked increase of proteoglycan sulfation was observed in dtd newborns from NAC treated pregnancies compared to the placebo group paralleled by a partial rescue of the abnormal bone morphology.
In conclusion, these different mouse models have recapitulated key aspects of disease pathology and identified new fundamental mechanisms paving the way for developing potential therapeutic approaches.

Maurizio Molinari, Istituto di Ricerca in Biomedicina, Bellinzona, Svizzera

When Nov 28, 2017
from 12:00 PM to 01:30 PM
Where Tigem Auditorium "Vesuvius"
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Contact Phone 081-19230659
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Ido Amit, Ph.D. - "The power of ONE: Immunology in the age of single cell genomics"

Immunology Department , Weizmann Institute of Science, Rehovot, Israel
When Dec 19, 2017
from 12:00 PM to 01:30 PM
Where Tigem Auditorium "Vesuvius"
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Contact Phone 081-19230659
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The power of ONE: Immunology in the age of single cell genomics Ido Amit Weizmann Institute of Science Immune cell functional diversity is critical for the generation of the different regulator and effector responses required to safeguard the host against a broad range of threats such as pathogens and cancer, but also from attacking its own healthy cells and tissues
In multi cellular organisms, dedicated regulatory circuits control cell-type diversity and responses.
The crosstalk and redundancies within these circuits and substantial cellular plasticity and heterogeneity pose a major research challenge.
Over the past few years, we have developed a collection of innovative single-cell technologies, which provide unprecedented opportunities to draw a more accurate picture of the various cell types and underlying regulatory circuits, including basic mechanisms, transitions from normal to disease states and response to therapies. I will discuss some of our discoveries and how they change the current dogma in immune regulation as well novel technologies that combine single cell RNA-seq with CRISPR pooled screens and demonstrate the power of these approach es to probe and infer the wiring of mammalian circuits, fundamental to future engineering of immune cells towards desired responses, including immunotherapy