RR&D Senior Research Career Scientist Award Application

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This Senior Research Career Scientist application is submitted to support the research of Dr. Richard L. Lieber. Previous research, performed under VA support, has elucidated the anatomical and biomechanical properties of human skeletal muscles that are used in tendon transfer surgery. This surgery is used for patients with spinal cord injury and strokes to restore function that has been lost after the injury. A functioning muscle is surgically moved to a new position where function was lost. Biomechanical modeling is also used to develop quantitative indices that allow surgeons to choose the remaining functioning muscle that is closest in physiological properties to the one that has been lost. The result is improved patient function after surgery and objective criteria for choice of surgical approach. Lieber’s group has also developed a novel, intraoperative laser diffraction device that can measure the detailed, microscopic properties of human muscles during surgery. This device works based on the interference between laser light and the anisotropic protein bands within the muscle fibers themselves. Since the spacing of these bands is related to muscle force, optical diffraction from muscle fibers provides insights into muscle function in a way that does not damage the fibers. These studies have not only revealed the normal operating range of many human muscles but they have been used to discover previously unknown muscle properties that occur after contracture. Muscle contractures, that may occur after stroke, head injury, spinal cord injury or muscular dystrophy, can be painful, limit range of motion and are difficult and expensive to treat. The muscle structural changes measured by Lieber and colleagues indicate that “contractured muscle” is limited in its ability to grow both in the longitudinal direction (limiting range of motion) and in the radial direction (limiting strength). Insights into the biological basis for this growth limitation was recently revealed when these investigators demonstrated that the muscle resident stem cell population was dramatically reduced in contractures and that the remaining stem cells did not develop normally but remained in an immature, hyperproliferative state. These observations have opened the way to a new line of research using various FDA-approved drugs that affect stem cells and can be applied to novel patient populations. In this way, rapid translation from laboratory to clinic can be made by avoiding the many regulatory hurdles associated with new drug approval. Taken together, the combination of anatomical, biomechanical and biological studies of human muscles has benefitted our VA patients both in terms of surgical and medical treatment and now in terms of making diagnoses and tracking therapeutic interventions. Future support is expected to continue this trajectory as the VA investment in human research yields actionable outcomes for clinicians treating these patients.