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Mestroni Lab

Genetics of Cardiac Muscle Diseases



Since 1991, we have collected clinical information and DNA of 2000 subjects from families with cardiomyopathies in the USA in Europe (Italy). Data and materials are collected in the NIH funded International Familial Cardiomyopathy Registry, which has been supported by various grants of the NIH, AHA, UN, MDA. Through our researches on the molecular genetics of cardiomyopathies and analysis on genotype-phenotype correlations, several genes and pathways causing heart disease have been investigated in my laboratory, from cytoskeletal and sarcomeric genes, to ion channels. We are interested in the genes causing dilated cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVD/C), left ventricular noncompaction and hypertrophic cardiomyopathy. Among the most important accomplishments are the discovery of several cardiomyopathy genes including the lamin A/C (LMNA) associated with variable muscular involvement, the cardiac sodium channel (SCN5A), the giant titin gene (TTN), the largest gene of the human genome, and the recent discovery of filamin C (FLNC). 

We are also interested in genotype-phenotype association studies, which are critical to transfer bench-to-bedside knowledge. Our ongoing research has shown that specific genes may have a different prognosis and suggest different management strategies.

Genomics of Cardiomyopathies
Functional studies of mutant cardiomyopathy genes are also performed to evaluate the consequences of the defective proteins on cellular models. We are using cardiac cellular model and zebrafish model organisms to recapitulate the mutant phenotype, following gene discovery in our genetic studies. Zebrafish studies are done in collaboration with Dr. Debbie Garrity at Colorado State University. 

Nanobiotechnology
We are currently exploring applications of nanobiotechnology and bioengineering to the study of heart function and treatment of heart failure and cardiomyopathies. With the use of atomic force microscopy (AFM), in collaboration with scientists at the University of Trieste (Italy), we have discovered biomechanical changes at the nanoscale in cardiac cells carrying genetic mutations (lamin A/C gene). In addition, using nanobiotechnology, biophysics, cell biology and bioengineering, with a multidisciplinary approach in collaboration with our UCD Department of Bioengineering and nanoscientists at the University of Trieste (Italy), we are developing ‘next-generation’ smartbiomaterials for tissue engineering and cardiac repair.





Post-doctoral Students

- Teisha Rowland

- Brisa Pena Castellanos

PhD Graduate Student

Mary Sweet, HMGP Graduate student

MS Graduate Student

Rene Begay, BS

Visiting Cardiology Fellows

Andrea Cocciolo

Ilaria Puggia

Senior Personnel

- Sharon Graw, PhD. CGC, Study coordinator

- Dobromir Slavov, PhD, Laboratory manager

- Valentina Martinelli, PhD

2015
Arrhythmogenic Phenotype in Dilated Cardiomyopathy: Natural History and Predictors of Life-Threatening Arrhythmias.​ Spezzacatene A, Sinagra G, Merlo M, Barbati G, Graw SL, Brun F, Slavov D, Di Lenarda A, Salcedo EE, Towbin JA, Saffitz JE, Marcus FI, Zareba W, Taylor MR, Mestroni L; Familial Cardiomyopathy Registry. J Am Heart Assoc. 2015 Oct 16;4(10). pii: e002149. doi: 10.1161/JAHA.115.002149. PMID: 26475296

The Cardiomyopathy Lamin A/C D192G Mutation Disrupts Whole-Cell Biomechanics in Cardiomyocytes as Measured by Atomic Force Microscopy Loading-Unloading Curve Analysis.​Lanzicher T, Martinelli V, Puzzi L, Del Favero G, Codan B, Long CS, Mestroni L, Taylor MR, Sbaizero O. Sci Rep. 2015 Sep 1;5:13388. doi: 10.1038/srep13388. PMID: 26323789

AFM single-cell force spectroscopy links altered nuclear and cytoskeletal mechanics to defective cell adhesion in cardiac myocytes with a nuclear lamin mutation.​ Lanzicher T, Martinelli V, Long CS, Del Favero G, Puzzi L, Borelli M, Mestroni L, Taylor MR, Sbaizero O. Nucleus. 2015 Aug 26:0. PMID: 26309016

2014 
Analysis of long- and short-range contribution to adhesion work in cardiac fibroblasts: an atomic force microscopy study.​ Sbaizero O, DelFavero G, Martinelli V, Long CS, Mestroni L. Mater Sci Eng C Mater Biol Appl. 2015 Apr;49:217-24. doi: 10.1016/j.msec.2014.12.083. Epub 2014 Dec 27. PMID: 25686942

Genetic Causes of Dilated Cardiomyopathy.​ Mestroni L, Brun F, Spezzacatene A, Sinagra G, Taylor MR. Prog Pediatr Cardiol. 2014 Dec;37(1-2):13-18. PMID: 25584016

We are part of the NIH funded North American Arrythmogenic Right Ventricular Dysplasia/Cardiomyopathy Registry, in collaboration with Dr. Frank Marcus (University of Arizona), Dr. Jeff Towbin (Cincinnati Children Hospital/University of Tennessee), Dr. Jeff Saffitz (Harvard medical School) and Wojchiech Zareba (University of Rochester).

Our laboratory is funded by the NIH/NHLBI, NIH/NCATS Colorado CTSA, Fondation Leducq TNE, European Research Council, American Heart Association, John Patrick Albright Foundation.​

We are part of pilot trials to treat cardiomyopathies, such as the VANISH trial (HCM) and the Array-797 trial (DCM).​

Collaborations
Our laboratory is based on the collaboration between Co-Directors Dr. Mestroni and Dr. Taylor, who share the lead of the Molecular Genetics laboratory and the Adult Medical Genetic Program. We also collaborate with a network of local and international investigators, in particular investigators at the University of Trieste and Florence in Italy under the auspices of two bilateral agreements, the University of Arizona, the University of Heidelberg. Recently, our laboratory has been awarded by the prestigious Fondation Leducq Transatlantic Network of Excellence, where we investigate the origin and treatment of arrhythmogenic cardiomyopathy in collaboration with Dr. William McKenna​, University of London, Dr. AJ Marian, University of Texas Houston, Dr. Thomas Weber, Mount Sinai SOM NY, Dr. Orfeo Sbaizero, University of Trieste and Dr. Hans Clevers, Hubrech Institute (The Netherlands).