My research interests are in the field of cardiac mechanobiology, seeking to understand how the mechanical environment in the heart influences cell behavior and cardiac function throughout pediatric development and disease. I completed my PhD at Vanderbilt working with Dave Merryman focusing on fibroblast activation and inflammatory cell recruitment after myocardial infarction. I was excited for the opportunity to pursue postdoctoral training at Stanford, initially under the mentorship of Dr. Beth Pruitt in mechanical and bioengineering and Dr. Jim Spudich in biochemistry. My postdoctoral project has focused on the effect of myosin mutations which cause hypertrophic cardiomyopathy (HCM) using human induced pluripotent stem cell (hiPSC) derived cardiomyocytes. I have learned techniques for hydrogel micropatterning and quantification of cellular scale forces through traction force and FRET microscopy. I have also participated in many exciting collaborations across Stanford (with Dr. Alex Dunn and Dr. Sean Wu), as well as collaborators at different institutions. My background in biomedical engineering has informed my quantitative and systems-based approach to biological questions, and my current appointment in the medical school working with Dr. Dan Bernstein has provided me with the opportunity to learn more about the realities of clinical care in pediatric cardiology.
Member, Maternal & Child Health Research Institute (MCHRI)
Honors & Awards
Postdoctoral Fellowship, American Heart Association (01/01/2019-08/14/2021)
K99 Pathway to Independence, NIH NHLBI (08/15/2021-2022)
Master of Science, Vanderbilt University (2014)
Doctor of Philosophy, Vanderbilt University (2016)
Bachelor of Science, University of Virginia (2011)
Hypertrophic cardiomyopathy beta-cardiac myosin mutation (P710R) leads to hypercontractility by disrupting super relaxed state.
Proceedings of the National Academy of Sciences of the United States of America
2021; 118 (24)
Hypertrophic cardiomyopathy (HCM) is the most common inherited form of heart disease, associated with over 1,000 mutations, many in beta-cardiac myosin (MYH7). Molecular studies of myosin with different HCM mutations have revealed a diversity of effects on ATPase and load-sensitive rate of detachment from actin. It has been difficult to predict how such diverse molecular effects combine to influence forces at the cellular level and further influence cellular phenotypes. This study focused on the P710R mutation that dramatically decreased in vitro motility velocity and actin-activated ATPase, in contrast to other MYH7 mutations. Optical trap measurements of single myosin molecules revealed that this mutation reduced the step size of the myosin motor and the load sensitivity of the actin detachment rate. Conversely, this mutation destabilized the super relaxed state in longer, two-headed myosin constructs, freeing more heads to generate force. Micropatterned human induced pluripotent derived stem cell (hiPSC)-cardiomyocytes CRISPR-edited with the P710R mutation produced significantly increased force (measured by traction force microscopy) compared with isogenic control cells. The P710R mutation also caused cardiomyocyte hypertrophy and cytoskeletal remodeling as measured by immunostaining and electron microscopy. Cellular hypertrophy was prevented in the P710R cells by inhibition of ERK or Akt. Finally, we used a computational model that integrated the measured molecular changes to predict the measured traction forces. These results confirm a key role for regulation of the super relaxed state in driving hypercontractility in HCM with the P710R mutation and demonstrate the value of a multiscale approach in revealing key mechanisms of disease.
View details for DOI 10.1073/pnas.2025030118
View details for PubMedID 34117120
Molecular Mechanisms and Cellular Models of Hypertrophic Cardiomyopathy: Insights from a Surprising Mutation
CELL PRESS. 2021: 253A
View details for Web of Science ID 000629601401473
Engineering the Microenvironment for Heart Muscle Cell Mechanobiology
CELL PRESS. 2020: 154A
View details for Web of Science ID 000513023201022
Hypertrophic Cardiomyopathy Mutations With Opposite Effects on [latin sharp s]-myosin Biomechanics Show Similar Structural and Biomechanical Phenotypes in Human Induced Pluripotent Stem Cell Derived Cardiomyocytes (hipsc-cms)
LIPPINCOTT WILLIAMS & WILKINS. 2019
View details for Web of Science ID 000511467800091
- Engineering hiPSC cardiomyocyte in vitro model systems for functional and structural assessment PROGRESS IN BIOPHYSICS & MOLECULAR BIOLOGY 2019; 144: 3–15
Engineering hiPSC cardiomyocyte invitro model systems for functional and structural assessment.
Progress in biophysics and molecular biology
The study of human cardiomyopathies and the development and testing of new therapies has long been limited by the availability of appropriate invitro model systems. Cardiomyocytes are highly specialized cells whose internal structure and contractile function are sensitive to the local microenvironment and the combination of mechanical and biochemical cues they receive. The complementary technologies of human induced pluripotent stem cell (hiPSC) derived cardiomyocytes (CMs) and microphysiological systems (MPS) allow for precise control of the genetics and microenvironment of human cells in invitro contexts. These combined systems also enable quantitative measurement of mechanical function and intracellular organization. This review describes relevant factors in the myocardium microenvironment that affect CM structure and mechanical function and demonstrates the application of several engineered microphysiological systems for studying development, disease, and drug discovery.
View details for PubMedID 30579630
Mechanobiology of Myosin Mutations and Myofibril Remodeling in iPSC-Cardiomyocytes
CELL PRESS. 2018: 496A–497A
View details for Web of Science ID 000430563200233