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Research Focus

The focus of our research is the understanding and prevention of cell damage in systemic protein misfolding diseases. Transthyretin amyloidoses are characterized by the misfolding and deposition of the protein transthyretin (TTR) in several organs including heart, peripheral and autonomic nerves, kidney, gut, lung, eye, etc. In these diseases the protein is synthesized far from the site of deposition, thus, tissue and cell damage initiate outside the cell. We have established a human cardiac and neuronal tissue culture models to study the effects of externally applied recombinant human TTR at physiologic concentrations. We found that TTR variants that deposit in cardiac or neuronal tissue in vivo, are cytotoxic to the cells whereas non-amyloidogenic TTR variants are not. In the TTR amyloidoses it is not clear whether a particular event triggers TTR aggregation and deposition, or rather is the chronic exposure to the protein that results in the observed pathology. We have expanded our studies to chronic tissue culture systems in which we apply small TTR concentrations into the cells over long periods of time. We are characterizing the effects of such treatments using biochemical and microarray genomic technology to identify possible sites of pharmacologic intervention. We have also tested the polyphenol resveratrol and some of its structural analogs as potential inhibitors of TTR induced cytotoxicity in the human cardiomyocytes and neurons. These compounds were known to bind TTR and stabilize its native quarternary structure, thus preventing misfolding and aggregation of the protein. We have determined that there is more than one mechanism of cell damage prevention; our goal is to exploit all possible mechanisms for prevention and treatment of these devastating diseases.

Professional Experience

B.Sc. in Chemistry, University of Barcelona, Catalonia, Spain, 1992
M.Sc. in Organic Chemistry, University of Barcelona, Catalonia, Spain, 1994

Ph.D. in Organic Chemistry, University of Barcelona, Catalonia, Spain, 1998

Postdoctoral Fellow, Torrey Pines Institute for Molecular Studies, San Diego, CA, 1998-2000

Research Associate, The Scripps Research Institute, La Jolla, Ca, 2001-2005

Staff Scientist, The Scripps Research Institute, La Jolla, Ca, 2005-2006

Assistant Professor, The Scripps Research Institute, La Jolla, Ca, 2007-present

Awards & Professional Activities

1993-1997 Predoctoral Fellowship from the Catalan Government

1995 Catalan Chemical Society Award

1995 & 1996 Short-term Travel Awards, Catalan Government (ENS-CNRS at Paris, France)

2008-2010 American Heart Association Beginning-in-Aid Award

Selected References

Reixach, N., Deechongkit, S., Jiang, X., Kelly, JW., Buxbaum, JN. (2004) Tissue damage in the amyloidoses: Transthyretin monomers and nonnative oligomers are the major cytotoxic species in tissue culture. Proc Natl Acad Sci U S A., 101: 2817-22

Tagoe CE., Reixach, N., Friske, L., Mustra, D., French, D., Gallo, G., Buxbaum, JN. (2007) In vivo stabilization of mutant human transthyretin in transgenic mice. Amyloid, 14:227-236.

Reixach, N., Foss, T., Santelli, E., Pascual, J., Kelly, JW., Buxbaum, JN. (2008) Human-Murine Transthyretin Heterotetramers are Kinetically Stable and Non-amyloidogenic: A lesson in the generation of transgenic models of diseases involving oligomeric proteins. J Biol Chem, 283:2098-107.

Buxbaum JN., Reixach N. (2009) Transthyretin: the servant of many masters. Cell Mol Life Sci. 66:3095-101.