Journal of Computational Systems Biology

Modeling and assessing diaphragm mechanics: Investigation of the determinants of diaphragm muscle mechanics and kinematics, including the unique mechanical properties of the diaphragm and structural issues such as the geodesic properties of diaphragm muscle fibers. Current works describe numerous approaches to dealing with these determinants, including measuring diaphragm curvature, displacement and muscle shortening, as well as computational modeling of the effect of muscle anisotropic properties on diaphragm shape. This work is established in collaboration with Dr. Rolf Hubmayr at Mayo Clinic.

Modeling and assessing diaphragm function in disease: We have recently been interested in assessing diaphragm function in chronic obstructive pulmonary disease (COPD) patients. In particular, we are interested in assessing the effect of body mass index (BMI) on a realistic model of diaphragm structure in subjects with airflow obstruction. In addition, we hope to examine how body mass index affects the kinematics of the diaphragm and its interaction with the rib cage in subjects with airflow obstruction. Furthermore, we will determine the contrasting effects of lung volume reduction surgery (LVRS) and medical therapy on diaphragm and chest wall remodeling and whether BMI is a factor in mediating such effects in severe COPD subjects. This work is established in collaboration with Drs. Hanania and Sharafkhaneh, clinical investigators at Baylor College of Medicine as well as Dr. Eric Hoffman of Iowa University. Those collaborators are principal investigators of the ongoing COPDGene National Trial.

Assessment of respiratory muscle function in mouse models of muscular dystrophy: A complex rearrangement mutation in the mouse titin gene leads to an in-frame 83-amino acid deletion in the N2A region of titin. Autosomal recessive inheritance of the titin muscular dystrophy with myositis (Ttn(mdm/mdm)) mutation leads to a severe early-onset muscular dystrophy and premature death. We have tested the hypothesis that the titin N2A deletion in the mdm mouse diaphragm would have a deleterious impact on its force-generating capacity and would alter its passive mechanical properties, independent of major histopathology. Our data show significant structural and functional aberrations of the respiratory pump in the mdm mouse that may be attributable to a critical function of titin's N2A region. This work was part of the Ph.D. thesis of Dr. Michael Lopez who has been a member of our research group.

Mechanical signal transduction: We have been interested in the anisotropic regulation of the mechanosensitive genes, such as Ankrd2. We found that axial stretch activated Akt, which up-regulated Ankrd2 expression through NF-kappaB. However, stretch in the orthogonal direction to the muscle fibers activated Ras-GTP, Raf-1, and Erk1/2 proteins, which up-regulated Ankrd2 expression through AP-1. Our data show the anisotropic regulation of Ankrd2 gene expression in the diaphragm muscles occurs via two distinct mechanosensitive signaling pathways. This work was conducted in collaboration with my colleague Dr. Junaith Mohamed, a Research Associate who has been a member of our research group. In addition, we have been interested in the physiologic role of Sirt1 in skeletal muscles. We have recently unraveled a mechanism triggered by mechanical stretch of skeletal muscle cells that leads to an EGR1-dependent transcriptional activation of the Sirt1 gene. The resulting transient increase in SIRT1 expression generates an antioxidative response. This work was conducted in collaboration with my colleague Dr. Patricia Pardo, a Research Associate who has been a member of our research group