New preprint from our lab in collaboration with the Hlehouse and Soranno labs examining the troponin-T linker region that is a hotspot for cardiomyopathy mutations and variants of unknown significance.
Together, we used single molecule techniques, in vitro reconstitution assays, and molecular dynamics simulations to demonstrate that this linker region is intrinsically disordered and dynamic in the context of isolated troponin and the fully-regulated thin filament. We also demonstrate how rigorous tools developed by the intrinsically disordered protein field can provide new insights into the structural mechanisms underlying human cardiomyopathy mutations. Congratulations to all of our co-authors!
The paper can be found here.
Ella Mozier joins the lab as a graduate student
Welcome to Ella Mozier, a new graduate student in the lab who will be co-mentored with Andrea Soranno.
New Greenberg lab preprint in collaboration with the Garcia and Lavine labs
Familial dilated cardiomyopathy (DCM) is frequently caused by autosomal dominant point mutations in genes involved in diverse cellular processes, including sarcomeric contraction. While patient studies have defined the genetic landscape of DCM, genetics are not currently used in patient care, and patients receive similar treatments regardless of the underlying mutation. It has been suggested that a precision medicine approach based on the molecular mechanism of the underlying mutation could improve outcomes; however, realizing this approach has been challenging due to difficulties linking genotype and phenotype and then leveraging this information to identify therapeutic approaches. Here, we used multiscale experimental and computational approaches to test whether knowledge of molecular mechanism could be harnessed to connect genotype, phenotype, and drug response for a DCM mutation in troponin T, deletion of K210. Previously, we showed that at the molecular scale, the mutation reduces thin filament activation. Here, we used computational modeling of this molecular defect to predict that the mutant will reduce cellular and tissue contractility, and we validated this prediction in human cardiomyocytes and engineered heart tissues. We then used our knowledge of molecular mechanism to computationally model the effects of a small molecule that can activate the thin filament. We demonstrate experimentally that the modeling correctly predicts that the small molecule can partially rescue systolic dysfunction at the expense of diastolic function. Taken together, our results demonstrate how molecular mechanism can be harnessed to connect genotype and phenotype and inspire strategies to optimize mechanism-based therapeutics for DCM.
Preprint can be found here.
New Greenberg lab publication, lead by Dr. Ankit Garg, looking at mutations in skeletal muscle actin causing cardiomyopathy
Skeletal muscle actin mutations are well-known to cause skeletal myopathies, but their role in cardiomyopathies have been controversial as skeletal muscle actin is only expressed at modest levels in the heart. Here, we demonstrate that a skeletal muscle actin mutation potently causes multiple defects in actin function at the atomic and molecular scales, and it functions in a dominant fashion, leading to cardiomyocyte contractile defects. Our results establish how skeletal muscle actin mutations may cause cardiomyocyte dysfunction and lay the foundation for future studies of the role of skeletal muscle actin in cardiomyopathy. The paper can be found here.
Congratulations to all of the authors, including our collaborators: Drs. Silvia Jansen, Rui Zhang, and Kory Lavine.
New collaborative paper with Greenberg lab contributions looking at post-translational modifications that contribute to the regulation of skeletal muscle contraction
The preprint can be found here. Thank you to Gretchen Meyer and our other collaborators for including us.
New collaborative Greenberg Lab publication with the Hinson lab on titin truncation variants
Congratulations to all of the authors. The publication can be found here.
Congratulations to Dr. Ankit Garg!
Dr. Garg, a postdoc in the lab started a new position at Johns Hopkins and received a great score on his K08 grant from NHLBI!
New Publication with Dr. Brent Scoitt
Our latest publication is “Multiscale biophysical models of cardiomyopathies reveal complexities challenging existing dogmas”. Here, we describe how experimental and computational biophysical tools are being harnessed to study cardiomyopathies and how they are revealing new insights into the disease pathogenesis that challenge existing models. The article can be found here.
New Greenberg Lab Publication with Dr. Ankit Garg
New article with Dr. Ankit Garg, “Assessing Cardiac Contractility From Single Molecules to Whole Hearts”. We describe how multiscale tools can be harnessed to reveal new insights into heart failure. The article can be found here.