Small Molecule uPAR Agonists to Promote Recovery of Breathing in Chronic Spinal Cord Injury

Most spinal cord injury (SCI) cases are at the cervical level and result in the inability to breathe. Those injured are left reliant on a mechanical ventilator, which severely diminishes their quality of life and become dependent on specialized health care and management. Most experimental investigations to promote respiratory motor recovery have been in the immediate, acute stages of injury and with some promising results. However, most of the SCI population are at chronic state and it is not known if these effective acute therapies are applicable to them. To overcome this gap in knowledge, this application proposes to develop potential treatments in the chronic injured setting so that independent breathing function can be returned. We have found that there is very little spontaneous recovery of respiratory motor function after experimental cervical SCI so this proposal is both timely and important. One potential therapeutic approach is through enhancement of endogenous plastic mechanisms within the chronically injured SC. Recent studies using animal models of cervical SCI have shown that the urokinase system plays a critical role in the processes that lead to recovery of diaphragmatic activity. The urokinase system consists of a GPI-anchored protein the urokinase receptor (uPAR), a multi-domain serine proteinase known as urokinase (uPA), and the extracellular matrix component vitronectin (VTN). The VTN•uPAR•uPA complex promotes (i) proteolysis through uPA and (i) integrin signaling through VTN. Animal studies have demonstrated that recovery of respiratory function is completely dependent on uPAR signaling. Small organic molecules that activate uPAR could provide leads to develop therapeutic agents to restore breathing in SCI patients. Towards achieving this goal, we bring together two research laboratories with highly complementary expertise. The Meroueh laboratory is primarily a chemical biology and medicinal chemistry laboratory and has recently discovered a small-molecule agonist of uPAR (XHS-42). The Alilain group has well-established animal models of respiratory motor insufficiency after SCI. In the first aim of this proposal, the Meroueh lab will enhance the potency and solubility of XHS-42 through chemical design and synthesis. In the second aim, the most promising 1-2 derivatives will be explored in animal models of chronic SCI by the Alilain laboratory. Collectively these experiments are expected to generate leads that will be optimized in future studies to generate therapeutic agents that restore respiratory motor recovery of the chronic SCI community and thereby improve their quality of life.