Gourraud P.-A.,University of California at San Francisco |
Gilson L.,SupBiotech |
Girard M.,CECS I STEM |
Peschanski M.,French Institute of Health and Medical Research
Stem Cells | Year: 2012
Among the tools of regenerative medicine, induced pluripotent stem cells (iPSCs) are interesting because the donor genotype can be selected. The construction of banks of iPSC cell lines selected from human leukocyte antigen (HLA) homozygous donors has been proposed to be an effective way to match a maximal number of patients receiving cell therapy from iPSC lines. However, what effort would be required to constitute such a bank for a worldwide application has remained unexplored. We developed a probabilistic model to compute the number of donors to screen for constituting banks of best-chosen iPSC lines with homozygous HLA haplotypes (haplobanks) in four ancestry backgrounds. We estimated what percentage of the patients would be provided with single HLA haplotype matched cell lines. Genetic diversity leads to different outcomes for the four sets in all terms. A bank comprising iPSC lines representing the 20 most frequent haplotypes in each population would request quite different number of donors to screen, between 26,000 for European Americans and 110,000 for African Americans. It would also match different fractions of the recipient population, namely, more than 50% of the European Americans and 22% of African Americans. Conversely, a bank comprising the 100 iPSC lines with the most frequent HLA in each population would leave out only 22% of the European Americans, but 37% of the Asians, 48% of the Hispanics, and 55% of the African Americans. The constitution of a haplobank of iPSC lines is achievable through a large-scale concerted worldwide collaboration. © AlphaMed Press.
Jarray R.,SupBiotech |
Jarray R.,CEA Fontenay-aux-roses |
Pavoni S.,CEA Fontenay-aux-roses |
Borriello L.,University of Paris Descartes |
And 15 more authors.
Biochimie | Year: 2015
Significant interest has recently emerged for phosphatase and actin regulatory protein (PHACTR1) gene in heart diseases prognosis. However, the functional role of phactr-1 protein remains elusive in heart related-diseases such as atherosclerosis, coronary artery calcification, ischaemic stroke, coronary artery stenosis and early-onset myocardial infarction. Phactr-1 is directly regulated by vascular endothelial growth factor A165 (VEGF-A165) through VEGF receptor 1 (VEGR-1) and Neuropilin-1 (NRP-1). Using an antagonist peptide approach to inhibit the interaction of VEGF-A165 to NRP-1 and VEGF-R1, we highlighted the importance of both cysteine residues located at the end of VEGF-A165 exon-7 and at the exon-8 to generate functional peptides, which decreased Phactr-1 expression. Here, we report original data showing Phactr-1 down-expression induces the expression of Matrix Metalloproteinase (MMP) regulators such as Tissue inhibitor of metalloproteinase (TIMP-1/-2) and Reversion-inducing-cysteine-rich protein with kazal motifs (RECK). Furthermore, focal adhesion kinases (FAK/PYK2/PAXILLIN) and metabolic stress (AMPK/CREB/eNOS) pathways were inhibited in endothelial cells. Moreover, the decrease of phactr-1 expression induced several factors implicated in atherosclerotic events such as oxidized low-density lipoprotein receptors (CD36, Clusterin, Cadherin-13), pro-inflammatory proteins including Thrombin, Thrombin receptor 1 (PAR-1), A Disintegrin And Metalloprotease domain-9/-17 (ADAM-9/-17), Trombospondin-2 and Galectin-3. Besides, Phactr-1 down-expression also induces emerging atherosclerosis biomarkers such as semicarbazide-sensitive amine oxidase (SSAO) and TGF-beta-inducible gene h3 (βIG-H3). In this report, we show for the first time the direct evidence of the phactr-1 biological function in the regulation of pro-atherosclerotic molecules. This intriguing result strengthened heart diseases PHACTR-1 single-nucleotide polymorphisms (SNP) correlation. Taken together, our result highlighted the pivotal role of phactr-1 protein in the pathogenesis of atherosclerosis. © 2015 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.
Carbonell P.,French National Center for Scientific Research |
Methods in Molecular Biology | Year: 2015
Computational protein design, a process that searches for mutants with desired improved properties, plays a central role in the conception of many synthetic biology devices including biosensors, bioproduction, or regulation circuits. To that end, a rational workflow for computational protein design is described here consisting of (a) searching in the sequence, structure or chemical spaces for the desired function and associated protein templates; (b) finding the list of potential hot regions to mutate in the parent proteins; and (c) performing in silico screening of mutants with predicted improved properties. © Springer Science+Business Media New York 2015.
Carbonell P.,University of Évry Val d'Essonne |
Carbonell P.,French National Center for Scientific Research |
Carbonell P.,University Pompeu Fabra |
Drug Discovery Today: Technologies | Year: 2014
Prediction tools are commonly used in pre-clinical research to assist target selection, to optimize drug potency or to predict the pharmacological profile of drug candidates. In silico prediction and overcoming drug resistance is a new opportunity that creates a high interest in pharmaceutical research. This review presents two main in silico strategies to meet this challenge: a structure-based approach to study the influence of mutations on the drug-target interaction and a system-biology approach to identify resistance pathways for a given drug. In silico screening of synergies between therapeutic and resistant pathways through biological network analysis is an example of technique to escape drug resistance. Structure-based drug design and in silico system biology are complementary approaches to reach few objectives at once: increase efficiency, reduce toxicity and overcoming drug resistance. © 2014 Elsevier Ltd.
PubMed | SupBiotech and University of Évry Val d'Essonne
Type: | Journal: Frontiers in bioengineering and biotechnology | Year: 2014
Synthetic biology aims at translating the methods and strategies from engineering into biology in order to streamline the design and construction of biological devices through standardized parts. Modular synthetic biology devices are designed by means of an adequate elimination of cross-talk that makes circuits orthogonal and specific. To that end, synthetic constructs need to be adequately optimized through
PubMed | SupBiotech
Type: | Journal: Methods in molecular biology (Clifton, N.J.) | Year: 2013
The focus of this chapter is on the important concepts behind the in silico techniques that are used today to assess target druggability. The first step of the assessment consists of finding cavity space in the protein using 2D and/or 3D topological concepts. These concepts underlie the geometry and energy-based pocketfinder algorithms. Analysis pursues on the physico-chemical complementarity between the binding site and the drug like molecule. Geometrical and molecular flexibility aspect are also included in this assessment. The presence of hot interaction spots are shown to be particularly important for targeting protein-protein interactions. Finally, binding site promiscuity can be assessed by large scale structural comparison with other targets. Common chemical features amongst protein cavities can predict potential cross-reactivity with unwanted targets.