Our research focuses on studying disorders of the diaphragm and other breathing muscles. The respiratory muscles pump air into and out of the lungs, and when these muscles are defective this can lead to respiratory failure and even death. Some disorders of the respiratory muscles are genetic in origin. This is the case for muscular dystrophies such as Duchenne Muscular Dystrophy and many other inherited diseases of skeletal muscle. In other patients, weakness of the respiratory muscles is not genetically determined but instead acquired due to another illness. This is especially frequent in critically ill individuals who become dependent upon mechanical ventilation in the intensive care unit, due to a condition called Ventilator-Induced Diaphragmatic Dysfunction. We are investigating the cellular and molecular mechanisms which contribute to these diseases, with an emphasis on translating these changes to the overall physiologic function and strength of the muscles. Our primary goal is to develop novel therapies that will help to reverse and/or prevent the development of respiratory muscle weakness and failure in patients.

Therapeutic modulation of innate immunity in genetic muscle disease involving the diaphragm:

We have shown that modulation of innate immune mechanisms (e.g., chemokine receptors or Toll-like receptors) leads to dramatic improvements in contractile function as well as reduced muscle fibrosis in the standard murine model of Duchenne Muscular Dystrophy (DMD), the mdx mouse. The mdx mouse model is a genetic homologue of human DMD and our studies have largely focused on the diaphragm because it is the most severely affected muscle. Macrophages constitute by far the predominant inflammatory cell type within DMD and mdx muscles, where they exhibit different phenotypic profiles typified by “polarization” towards inflammatory (M1) or alternatively activated/anti-inflammatory (M2) phenotypes. Other immune cell types are also increased within dystrophic muscles and can additionally modulate or be modulated by macrophage function. Our basic premise is that effective muscle repair depends upon maintaining an appropriate M1/M2 balance of macrophage properties; excessive skewing in either direction is predicted to be harmful. Given that the M1/M2 balance within muscle is a complex and dynamic phenomenon which changes during the course of disease, we are testing the hypothesis that immune modulation by drug therapy needs to be specifically tailored to disease stage, guided by novel immune-based biomarkers. Therefore, rather than the current “one size fits all” approach to DMD pharmacotherapy which consists of treatment with corticosteroids, we propose that a precision medicine approach (“Giving the right drug to the right patient at the right time”) can more effectively alter inflammatory and fibrogenic mechanisms.

Diaphragmatic dysfunction acquired in the intensive care unit:

Patients in the intensive care unit (ICU) frequently develop severe muscle weakness and atrophy, particularly when they require artificial respiratory support by mechanical ventilation. We have demonstrated in both animal models and humans that this process preferentially affects the diaphragm in a phenomenon known as Ventilator-Induced Diaphragmatic Dysfunction (VIDD). We are building upon this work by performing patient-based physiological and discovery research in human patients, in combination with mechanistic studies in cell culture and animal models. We believe that there are at least two distinct stages consisting of: 1) an early phase dominated by mitochondrial dysfunction, oxidative stress, and exaggerated activation of innate immunity; and 2) a late phase characterized by impaired myogenesis in association with muscle atrophy, fibrosis and fatty infiltration. Our vision for the future involves translating this two-phase mechanistic framework into a clinically useful paradigm that can be exploited for diagnostic and therapeutic purposes. New biomarkers and diagnostic tools are being explored as a means of identifying individuals who are at a particular stage of the pathophysiologic process or at the greatest risk for skeletal muscle dysfunction. We intend to determine whether this information can be used to guide personally-tailored treatment and prevention strategies. To achieve these goals, we have assembled a unique set of techniques and tools including: 1) assessment of diaphragm muscle function at the whole organ level (via non-painful magnetic stimulation of phrenic nerves) as well as at the single fiber level in muscle biopsies obtained during surgery from patients; 2) diaphragm imaging methods to permit quantification of muscle volume, geometry, and density (reflective of fat content) in humans; 3) state-of-the-art proteomics and metabolomics experimental approaches; and 4) unique animal models with genetic modifications of the key pathways involved in the pathogenesis of VIDD.