TAT-Mediated Transduction of MafA Protein In Utero Results in Enhanced Pancreatic Insulin Expression and Changes in Islet Morphology

Alongside Pdx1 and Beta2/NeuroD, the transcription factor MafA has been shown to be instrumental in the maintenance of the beta cell phenotype. Indeed, a combination of MafA, Pdx1 and Ngn3 (an upstream regulator of Beta2/NeuroD) was recently reported to lead to the effective reprogramming of acinar cells into insulin-producing beta cells. These experiments set the stage for the development of new strategies to address the impairment of glycemic control in diabetic patients. However, the clinical applicability of reprogramming in this context is deemed to be poor due to the need to use viral vehicles for the delivery of the above factors. Here we describe a recombinant transducible version of the MafA protein (TAT-MafA) that penetrates across cell membranes with an efficiency of 100% and binds to the insulin promoter in vitro. When injected in utero into living mouse embryos, TAT-MafA significantly up-regulates target genes and induces enhanced insulin production as well as cytoarchitectural changes consistent with faster islet maturation. As the latest addition to our armamentarium of transducible proteins (which already includes Pdx1 and Ngn3), the purification and characterization of a functional TAT-MafA protein opens the door to prospective therapeutic uses that circumvent the use of viral delivery. To our knowledge, this is also the first report on the use of protein transduction in utero

The podocyte as a target for therapies-new and old

Injury to the podocyte results in proteinuria and often leads to progressive kidney disease. As podocytes have limited ability to repair and/or regenerate, the extent of podocyte injury is a major prognostic determinant in diabetic nephropathy and other common causes of end-stage renal disease. Therapies aimed at preventing or limiting podocyte injury and/or at promoting podocyte repair or regeneration therefore have major potential clinical and economic benefits. Many current therapies-including glucocorticosteroids and calcineurin antagonists-have potent effects on podocytes. The nonspecific natures of these agents lead to undesirable systemic adverse effects: an agent with a more specific focus on podocytes would cause less treatment-associated morbidity. Recent years have seen dramatic advances in our understanding of podocyte biology and in particular regulation of its actin cytoskeleton, the major determinant of the complex architecture on which these cells depend for their function. This advance has allowed the identification of potential therapeutic targets and the next few years should see the development and testing of specific therapies aimed at the podocyte. Thus we are about to move from a situation where some of our 'blunderbuss' older therapies fortuitously happened to have beneficial effects on podocytes to a new era where advances in biological knowledge about a key cell type in the kidney will allow targeted drug design. As well as being intellectually more satisfying, every reason exists to believe that patients of the future will benefit and that the scourge of progressive kidney disease will be more effectively tackled. © 2011 Macmillan Publishers Limited. All rights reserved.link_to_subscribed_fulltex

Transdisciplinary approach to restore pancreatic islet function

The focus of our research is on islet immunobiology. We are exploring novel strategies that could be of assistance in the treatment and prevention of type 1 diabetes, as well as in the restoration of metabolic control via transplantation of insulin producing cells (i.e., islet cells). The multiple facets of diabetes and β-cell replacement encompass different complementary disciplines, such as immunology, cell biology, pharmacology, and bioengineering, among others. Through their interaction and integration, a transdisciplinary dimension is needed in order to address and overcome all aspects of the complex puzzle toward a successful clinical translation of a biological cure for diabetes