Small Molecules to Restore Breathing Following Spinal Cord Injury

Grants and Contracts Details


A major cause of death among spinal cord injury (SCI) patients is from pneumonia, pulmonary emboli, and septicemia. These factors can be attributed to (i) directly to the weakening of the respiratory muscles; or (ii) indirectly as a result of putting patients on mechanical ventilator support. Weakness of respiratory muscle function is often attributed to interruption of the descending bulbospinal respiratory pathways as a result of cervical spinal cord injury, especially when it occurs rostal to the phrenic nucleus. Remarkably, some patients recover respiratory function following SCI in a process known as the crossed phrenic phenomenon (CPP). This process is a testament of the remarkable plasticity of the spinal cord. Deeper understanding of this plasticity is essential for the development of therapeutic agents to restore breathing in SCI patients. Recent studies using animal models of CPP have shown that the plasminogen system plays a critical role in the processes that lead to CPP. The plasminogen system consists of a cell surface GPI-anchored protein known as the urokinase receptor (uPAR), a multi-domain serine proteinase known as uPA, and the extracellular matrix component vitronectin (VTN). The VTN•uPAR•uPA ternary complex promotes (i) proteolysis through uPA and (i) integrin signaling through VTN. Animal studies have demonstrated that the CPP is independent of uPA catalytic activity but completely dependent on signaling mediated by its protein-protein interaction with uPAR. Small organic molecules that modulate the uPAR•uPA protein-protein interactions could provide valuable chemical probes to explore the role of uPAR in CPP and lead compounds to develop therapeutic agents to restore breathing in SCI patients.
Effective start/end date12/1/156/30/17


  • Indiana University: $54,107.00


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