The LCN – Leducq Cytoskeletal Network

2021

Dr. Prosser will co-lead a Leducq Transatlantic Network of Excellence on the cytoskeletal role in cardiomyocyte health and disease. Leducq networks brings together investigators from all over the world to tackle the leading challenges in cardiovascular research.
Our network consists of the labs of Drs. Ken Margulies (Penn), Giulio Agnetti (Hopkins) and Ben Prosser (Penn) in the U.S., and Drs. Lucie Carrier (co-lead, Hamburg), Jolanda van der Velden (Amsterdam), Izhak Kehat (Israel) and Marie-Jo Moutin (France). Sabrina Benitez at Penn will function as the network administrator. For more on our mission, check out the press release at the attached link.


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Insights into the nuclear mechanobiology of the heart

2021

Three recent publications from our lab and collaborators shed insight into how physical forces affect the shape and function of cardiomyocyte nuclei, with a specific focus on the nuclear lamina. The first study, led by the Discher lab (Cho et al., Dev Cell 2019), describes how the nuclear lamina acts to sense its mechanical environment and protect the nucleus from mechanical stress. Our work (Heffler et al. Circ Res 2020) went on to show how microtubules and intermediate filaments maintain a force balance on the lamina, and how disrupting desmin compromises this balance and leads to nuclear collapse. The most recent work, led by the Jain lab (Cell Stem Cell 2021), reveals how pathogenic variants in LMNA (the gene that encodes for the core structural element of the lamina) disrupt interactions between the lamina and chromatin to drive tissue-specific pathologies. Check out the papers in the links below.


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The ENDD Therapeutics Team

2021

We're thrilled to announce the formation of the ENDD Therapeutics Team, a multi-disciplinary group of investigators focused on developing new therapies for Epilepsy and Neuro-Developmental Disorders (ENDD).
The core labs include the Prosser and Heller Labs at Penn and the Davidson Lab at CHOP. We also work closely with Debbie French and the Human Pluripotent Stem Cell Core at CHOP to develop iPS-models of NDD and test novel therapies, and with Dr. Ingo Helbig, a neurogeneticist at CHOP, as our clinical consultant.
The group is focused on developing anti-sense oligonucleotide (ASO), small molecule, and CRISPR-based strategies for the treatment of NDD, with our initial focus on STXBP1- and SYNGAP1-related disorders. The ENDD team is supported by collaborations with the pharmaceutical and biotechnology sector, private foundations including the Syngap Research Fund and STXBP1 Foundation, and philanthropic efforts.


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Antisense oligonucleotide disruption of microRNA binding to treat STXBP1 encephalopathy

2021

Our team has developed a novel antisense approach to increase gene products that cause disease due to haploinsufficiency. We use site-blocking oligonucleotides (SBOs) to prevent microRNA-based repression of a target gene, "releasing the brake" on a particular gene of interest that is deficient in pathological states. In proof-of-concept studies, we show how disrupting microRNA repression of STXBP1 is capable of upregulating gene and protein expression to levels that are predicted to be therapeutic. We are currently pursuing this strategy for genes that cause neurodevelopment disorders due to haploinsufficiency. Check the linked abstract to see more!


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A balance of cytoskeletal forces maintains nuclear architecture in the cardiomyocyte

2020

Julie Heffler's cover article in Circulation Research describes how a balance of cytoskeletal forces is required to maintain the integrity of the nucleus of the heart cell. Her work shows that desmin intermediate filaments and their attachments to the nucleus are critical for nuclear homeostasis, and shed light on how disruptions to desmin may lead to "desminopathies", a diverse group of cardiac and skeletal muscle disorders. Click on the link to view the full article!


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Microtubules increase diastolic stiffness in human myocardium

2020

Stiffening of the myocardium and diastolic dysfunction is a prevalent and intractable feature of several types of heart failure. Matt Caporizzo's work demonstrates that microtubules contribute to this stiffening in patient myocardial tissue, and that depolymerizing microtubules can improve diastolic mechanics. His work also indicates that the microtubule contribution to diastolic mechanics becomes less prevalent with large stretches and in heavily fibrotic tissue, where other factors likely contribute more to myocardial stiffness. This work helps refine a patient target population that may benefit from a microtubule based therapy. Click on the link for the full text!


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Discovery of vasohibin 1 as a regulator of heart cell relaxation

2020

In a co-authored manuscript by Christina and Alex (Chen and Salomon, Circulation Research 2020), we describe how VASH1 serves as the primary detyrosinating enzyme in heart muscle cells. We further go on to show how suppressing VASH1 is sufficient to lower stiffness and improve myocyte contraction and relaxation in heart failure. This work pinpoints VASH1 as a novel therapeutic target for the treatment of cardiomyopathy, particularly those characterized by impaired relaxation or diastolic dysfunction.


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Cardiac microtubules in health and heart disease

2019

Matt Caporizzo and Christina Chen provide a comprehensive review on the role of microtubules in the cardiomyocyte - their contribution to various homeostatic and mechanical functions in the cell, and how these may be altered in disease. The work also highlights the many unknowns regarding the diverse roles of microtubules in the heart. Click the link for full text!


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Suppressing detyrosinated microtubules improves contractility in human heart failure

2018

Work by Chen et al. demonstrates two key findings: 1) that there is a proliferation and stabilization of microtubules and intermediate filaments in human heart failure, regardless of disease origin. 2) that suppressing detyrosinated microtubules with either genetic or pharmacologic approaches can rescue the contractile function of heart cells from patients with heart failure, about 40-50% back to "normal." This work highlights detyrosinated microtubules as a promising therapeutic target for the treatment of heart failure.
Click on the link to read the paper, or check out the press release here : http://www.newswise.com/articles/view/695927/


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Detyrosinated microtubules buckle and bear load in contracting cardiomyocytes

2016

Our work, in collaboration with folks in Engineering (Caporizzo, Shenoy groups) and Medicine (Margulies), shows that microtubules buckle and bear compressive load in a beating cardiomyocyte. The ability of microtubules to function as molecular shock absorbers is graded by "detyrosination", a post-translational modification of tubulin. Further, we found that detyrosination is increased in cardiomyopathy and correlates with functional decline in certain patient populations. The Prosser lab is actively investigating the efficacy of targeting detyrosination therapeutically to improve cardiac function in heart disease. Patrick Robison is the first author on this manuscript published in Science (a full text link is provided below).


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