MICHAEL MARDEN


Email: michael.marden@inserm.fr

Blood substitutes and pathologies related to protein polymerization

Three main axes of research are developed: blood substitutes, globin functions with neuroglobin as model, and the role of the a-Hb chaperone in the physiology of RBC. With research at the protein level, we make use of the tools of genetic engineering and functional studies based on time resolved optical techniques and nanotechnology. Our goal is to apply a fundamental understanding of the various protein states and transitions to improve the detection and treatment of clinical cases.

Blood substitutes

The lack of a sufficient supply of donated blood has led to new perspectives of producing a Hemoglobin (Hb) based blood substitute. In order to produce a sufficient quantity, we made the first production of human Hb in transgenic tobacco plants (patented). In order to increase the size of the molecule, we developed a stable octameric recombinant Hb by the introduction of surface cysteines.  Another strategy to increase the size is the use of core-crown nanoparticles, originally developed for drug delivery.

Neuroglobin (Ngb) and Redox systems

We study new human globins such as neuroglobin (expressed in neural cells), which displays a new mechanism of oxygen binding in competition with the reversible binding of the distal Histidine. We also study globins from invertebrate species, which display other functions such as a protective role against ROS and RNS species.  The spectroscopic methods developed to study these systems are often applicable to other cases, and through specific collaborations, we have expanded our studies to other proteins. Our time-resolved and static spectroscopic methods allow us to decipher specific ligand binding and electron transfer mechanisms. The dynamic light scattering technique used for size and surface charge characterization of the nanoparticles is also highly useful for studies of protein-protein interaction and polymerization, such as the interaction between Ngb and the protein prion, and the formation of HbS fibers.

Role of the a-hemoglobin stabilizing protein (AHSP), in the physiology of the RBC

AHSP specifically binds to a-Hb until association with b-Hb chains. We study the AHSP/α-Hb complex, which exhibits a unique functional state intermediate to the R and T-Hb states.  We have described the first mutation in the AHSP gene associated with α-thalassemia-like syndromes. The role of AHSP in the physiopathology of the red blood cell (RBC) will also be investigated, in particular to develop a biological test to assess the free alpha-Hb pool as an index of clinical severity of beta-thalassemias (patented).