Professor Mark Buckley has received an NIH Research Project Grant (R01) for his project, "Modulation of Insertional Achilles Tendinopathy by Multiaxial Mechanical Strains.” Insertional Achilles tendinopathy (IAT) is a common and painful disease that responds poorly to conservative (i.e., non-operative) care. Improved outcomes for IAT patients require interventions that target its fundamental cause. Thus, this study aims to elucidate the patterns of mechanical strain (i.e., deformation) that cause and reverse IAT in vitro, and determine how to induce these strain patterns in vivo through exercise-based physical therapy. The findings of this study will motivate effective, targeted non-surgical therapies for IAT. Collaborators for this project include Alayna Loiselle (Orthopaedics and CMSR), Michael Richards (Surgery), Sam Flemister (Orthopaedics), John Ketz (Orthopaedics) and Tongtong Wu (Biostatistics).

Professor Buckley has been awarded a 2017 University Research Award to pursue a promising project that has the potential to eventually leverage external funding. He will evaluate two approaches to minimizing the loss of corneal endothelial cells during cornea transplants. The project is titled, "Protection of corneal endothelial cells from surgical trauma."

Abstract:

More than 65,000 vision-restoring corneal transplantations take place every year for individuals with corneal disease, corneal injury (e.g., from cataract surgery) and corneal scarring. Unfortunately, 30% of corneal grafts fail within 20 years. The most common reason for transplanted corneal grafts to fail is loss of corneal endothelial cells (CECs), the cells that line the inside of the cornea and pump fluid from it to maintain its transparency. Many of these cells are killed due to contact with tools and other materials during transplantation surgery. Thus, there is a need for new approaches that prevent CEC death during corneal grafting.

Using a custom testing platform developed in our laboratory, our preliminary experiments suggest that changes in the cytoskeleton (the network of structures within a cell that give it its shape) of CECs greatly protect these cells from injury due to mechanical contact. That is, when cells contain fewer stress fibers -- thick cytoskeletal filaments that, like muscle, exert a contractile force -- mechanical vulnerability is reduced. Based on these findings, we hypothesize treatments known to reduce the presence of stress fibers in cells will protect CECs from mechanical injury during corneal transplantation. In Aim 1, we will test whether chemical treatment with three agents that interfere with stress fibers -- BAPTA, blebbistatin and the anti-metabolite 5-fluorouracil -- reduces CEC death when the endothelium is contacted with a controlled force (simulating surgical manipulation). In Aim 2, motivated by the previous finding that fewer CEC stress fibers are observed in corneas preserved at low temperatures, we will test whether CECs are less vulnerable to mechanical trauma when the cornea is colder. This study is a key first step towards establishing chemical treatments (Aim 1) and maintenance of the cornea at cold temperatures during surgery (Aim 2) as promising methods to limit surgical trauma-associated CEC loss during corneal transplantation and reduce risk of graft failure. These approaches may also be applicable to other eye surgeries that can damage the corneal endothelium, including cataract surgery.

Professor Mark Buckley has received a pilot grant from the Center for Musculoskeletal Research for his research project, "The influence of chondrocyte mechano-protective adaptation on the progression of osteoarthritis.” Osteoarthritis (OA) – a painful and complex joint disease characterized by progressive degeneration of articular cartilage and surrounding tissues – is among the leading causes of disability in the United States. Yet, there are no FDA-approved treatments proven to stop or reverse OA and preserve joint health, suggesting that novel targets for OA interventions are needed. Though the complete etiology of OA is unknown, aberrant mechanical loads leading to cell death and catabolic activity are thought play a role in this pathology. To maintain homeostasis when confronted by sustained biochemical stimuli, cells have a well-characterized ability to moderate their response to these signals (e.g., through downregulation of a surface receptor). The Buckley lab's preliminary data suggests that chondrocytes can also rapidly moderate their sensitivity to sustained mechanical stimuli (e.g., during ambulation) to prevent cell death or abnormal (pathological) behavior. Hence, it may be possible to prevent or slow OA by enhancing this adaptive phenomenon, which we refer to herein as cytoprotective adaptation to mechanical stimuli (CAMS).

The lab's long-term goal is to develop translatable therapies that protect cartilage from degeneration through stimulation or enhancement of CAMS. To take the next step towards this goal, the objective herein is to rigorously characterize our in vivo cartilage injury model and employ this model to assess how CAMS impacts long-term OA progression. Based on the lab's preliminary data, the central hypothesis is that CAMS slows OA pathogenesis following a traumatic joint injury. The rationale for the proposed study is that identifying CAMS as a chondroprotective cellular process address the need for identification of new and promising targets of OA interventions.