Molecular Physiology and Biophysics

Background

Dr. Caporizzo received his Ph.D. in Materials Science engineering at the Univ. Pennsylvania in 2014. Matt joined Dr. Yale E. Goldman's lab at the Perelman School of Medicine at the Univ. Pennsylvania, where he built an interferometric scattering microscope and developed an analytical Markov model to describe the molecular motility of processive dimers which he applied to the bundle-selective motor myosin X.  In 2016, Matt joined Dr. Benjamin Prosser's lab as a Postdoc and studied  the contribution of the microtubule cytoskeleton to cardiac viscoelasticity.   In 2022, Dr. Caporizzo joined the University of Vermont Larner College of Medicine as an Assistant Professor where he is actively continuing his research on the molecular mechanisms that stiffen the failing heart and developing platform to test new therapies that reverse pathological stiffening.

Research Description

The Mechanics of Heart Failure

Even in the age of COVID-19, heart failure remains the leading cause of death in developed countries. While drugs can alleviate symptoms, there is no proven therapy to repair failing hearts. Complicating the situation, heart failure is highly diverse as patients exhibit varying degrees of mechanical, metabolic, and electrical dysfunction. However, most patients present with impaired left-ventricular filling, i.e. diastolic dysfunction, a thus-far therapeutically intractable symptom arising from increased ventricular stiffness. 

In heart failure, ventricular stiffening is a runaway train where external stress throttles multiscale remodeling of myofilaments, the myocyte cytoskeleton and the extracellular matrix (ECM) that collectively impair cardiac function. External stress is sensed by the myocardium which responds by remodeling its ECM, the ECM in turn signals cardiomyocytes to alter their contractile performance and remodel their cytoskeleton. Yet in patients with heart failure, removing stress seldom reverses pathological remodeling. This is because signaling between pathologically remodeled cardiomyocytes and ECM continue to reinforce each other’s disease state. Much remains unknown about the molecular mechanisms of this cross-talk which makes it difficult to target therapeutically.

Our research focuses on understanding the molecular mechanisms that stiffen the heart, relating these changes to organ level physiology and developing therapies that reverse cardiac stiffening in heart disease.

Faculty Highlighted Publications

McAfee Q, Chen CY, Yang Y, Caporizzo MA, Morley M, Babu A, Jeong S, Brandimarto J, Bedi KC Jr, Flam E, Cesare J, Cappola TP, Margulies K, Prosser B, Arany Z. Truncated titin proteins in dilated cardiomyopathy. Sci Transl Med. 2021 Nov 3;13(618):eabd7287. doi: 10.1126/scitranslmed.abd7287. Epub 2021 Nov 3. PMID: 34731015.

Caporizzo MA, Prosser BL. Need for Speed: The Importance of Physiological Strain Rates in Determining Myocardial Stiffness. Front Physiol. 2021 Jul 30;12:696694. doi: 10.3389/fphys.2021.696694. PMID: 34393820; PMCID: PMC8361601.

Shah PP, Lv W, Rhoades JH, Poleshko A, Abbey D, Caporizzo MA, Linares-Saldana R, Heffler JG, Sayed N, Thomas D, Wang Q, Stanton LJ, Bedi K, Morley MP, Cappola TP, Owens AT, Margulies KB, Frank DB, Wu JC, Rader DJ, Yang W, Prosser BL, Musunuru K, Jain R. Pathogenic LMNA variants disrupt cardiac lamina-chromatin interactions and de-repress alternative fate genes. Cell Stem Cell. 2021 May 6;28(5):938-954.e9. doi: 10.1016/j.stem.2020.12.016. Epub 2021 Feb 1. PMID: 33529599; PMCID: PMC8106635.

Chen CY, Salomon AK, Caporizzo MA, Curry S, Kelly NA, Bedi K, Bogush AI, Krämer E, Schlossarek S, Janiak P, Moutin MJ, Carrier L, Margulies KB, Prosser BL. Depletion of Vasohibin 1 Speeds Contraction and Relaxation in Failing Human Cardiomyocytes. Circ Res. 2020 Jul 3;127(2):e14-e27. doi: 10.1161/CIRCRESAHA.119.315947. Epub 2020 Apr 10. PMID: 32272864; PMCID:PMC7334093.

Mugnai ML, Caporizzo MA, Goldman YE, Thirumalai D. Processivity and Velocity for Motors Stepping on Periodic Tracks. Biophys J. 2020 Apr 7;118(7):1537-1551. doi: 10.1016/j.bpj.2020.01.047. Epub 2020 Feb 25. PMID: 32367805; PMCID: PMC7136348.

Caporizzo MA, Chen CY, Bedi K, Margulies KB, Prosser BL. Microtubules Increase Diastolic Stiffness in Failing Human Cardiomyocytes and Myocardium. Circulation. 2020 Mar 17;141(11):902-915. doi:10.1161/CIRCULATIONAHA.119.043930. Epub 2020 Jan 16. PMID: 31941365; PMCID:PMC7078018.

All Dr. Caporizzo's Publications on Google Scholar