Friday Science Talks 2018

Microtubule Mechanotransduction Tunes Musculoskeletal Function 

Christopher W. Ward, PhD
Associate Professor, Department of Orthopedics, University of Baltimore

For the past 16 years my research program has focused on the mechanisms by which local calcium (Ca2+) signals contribute to physiological and pathological adaptations in striated muscle. Since 2009, I have focused much attention on the mechanisms by which mechanotransduction modulates local Ca2+ signaling. Our initial discoveries were in heart where we revealed that microtubules (MT) were essential cytoskeletal elements for the activation of stretch activated Ca 2+ sparks. To enable new discoveries in heart and skeletal muscle we developed novel research tools for the mechanical manipulation of single enzymatically isolated muscle cells.

Enabled by our novel techniques we discovered a MT mechanotransduction pathway in striated muscle which linked the mechanical force of stretch/contraction to a burst of reactive oxygen species (ROS) from NADPH oxidase2 (Nox2); a pathway we term X-ROS signaling. Our discoveries in both heart and skeletal muscle place Glu-tubulin, a post-translational modification (PTM) to a-tubulin, central to the regulation of MT dependent X-ROS mechanotransduction in health. Furthermore, we link the disease dependent increase in MT density and its level of Glu-modified tubulin to the deleterious excess in X-ROS and Ca2+ signals that underscore workload injury in dystrophic heart and skeletal muscle. The significance of our findings was seen when acute in vivo targeting of Glu-tubulin effectively protected both skeletal muscle and heart from workload induced contraction injury in the mdx model of Duchenne muscular dystrophy (DMD). Our recent work focuses on extending our acute MT targeted interventions to chronic trials, testing the hypothesis that these treatments will have a broad impact on muscle function.

In other work, we have transitioned to bone where the mechanisms linking mechanical cues to bone formation are not fully defined. Here we have identified MT mechanotransduction through X ROS as an integral pathway that regulates the mechano-responsiveness of osteocytes to regulate bone formation.

ALS Research After the Ice (Bucket) Age: What Have Learned, What Are We Doing & What Comes Next?

Lyle Ostrow, MD, PhD
Assistant Professor of Neurology, Neuromuscular Division, John Hopkins University School of Medicine; Assistant Professor of Pathology, John Hopkins University School of Medicine; Neurology Inpatient Service Attending Physician, John Hopkins Hospital

Dr. Ostrow is an Assistant Professor of Neurology and Pathology at Johns Hopkins. He received his MD. and a PhD in Biophysics from the State University of New York at Buffalo, followed by Medicine Internship, Neurology Residency and a Neuromuscular Medicine Fellowship at Johns Hopkins. Dr. Ostrow’s clinical practice and basic science research are focused on ALS. He serves on the Programmatic Panel for the Department of Defense ALS Research Program and on several committees and review panels for the ALS Association, the Northeast ALS Consortium, the New York Genome Center ALS Initiative, the Target ALS Foundation, ALSUntangled and others.

Dr. Ostrow established and directs the Target ALS Multicenter Human Postmortem Tissue Core, the first multi-center tissue bank specifically dedicated to ALS research. This Core integrates clinical and pathological data, tissue samples, biofluids, genetic analysis and slide imaging – all made broadly available to the ALS research community – in order to foster and accelerate collaborative ALS research amongst academia and industry researchers. Dr. Ostrow also recently completed a pilot clinical trial of PET imaging in ALS patients, and is directing a new collaborative ALS biomarker development effort involving several industry partners, non-profit foundations, and academic centers.