2. Local Delivery of Supplemental Agrin at the time of Injury Prevents Motor Endplate Degradation
Our lab has previously shown the novel finding that preservation of the NMJ after nerve injury actually improves functional recovery following reinnervation. Developmental neurobiology literature suggest that Agrin, a proteoglycan involved in synaptogenesis, may play a critical role in NMJ preservation. Our experiments with a murine model demonstrated that genetic deletion of MMP-3, a matrix-metalloproteinase that degrades agrin on a homeostatic basis, allowed sufficient agrin levels to remain in denervated motor endplates. Moreover, our lab further demonstrated that denervated motor endplates with sufficient agrin levels have superior morphometric qualities and are highly conducive to promoting successful reinnervation. Here, we seek to determine if direct local delivery of agrin after a traumatic nerve injury might preserve the motor endplates.
Current Projects
Overview
There are multiple strategies to improve functional recovery after a traumatic peripheral nerve injury. Once the nerve is injured and there is degradation of the axonal cytoskeleton, the process of Wallerian degeneration begins. In addtion, a series of degradative events also occur at the neuromuscular juction (NMJ) and at the muscle itself. These changes include the loss of pre-synaptic neural agrin as well as post-synaptic changes of the acetylcholine receptors which lose their mature "pretzel" morphology and regress into a immature "plaque" morphology. Once the NMJ is fully degraded, the chance for functional recovery is slim following any current method of surgical intervention. The muscle undergoes fibrosis and atrophy following denervation injury. Muscle fibrosis can be characterized by upregulation of TGFβ-1 and excess of deposition of extracellular matrix material, mainly collagen in the muscle. Muscle atrophy reduces the cross sectional area of the individual muscle fibers thus reducing the maximum force generation potential. Our fundamental questions include : how do these processes occur on a molecular level, can this degeneration be slowed or even reversed, and is there a role for pharmacological adjuncts to improve functional recovery?
1. Two-Photon Imaging of Human Neuromuscular Junction Degradation After Traumatic Peripheral Nerve Injury
Patients with traumatic nerve injuries to the brachial plexus (BPI) have particularly poor outcomes with limited functional recovery, even after optimal surgical management. As improvements in recovery have plateaued secondary to surgical manipulations alone, adjuvant cellular and molecular therapeutic regimens are required. Yet, the appropriate time to intervene can only be determined if there is a true understanding of the process of nerve and muscular degeneration secondary to a traumatic nerve injury. While animal models have shed light on molecular changes to the muscle and motor endplate post-injury, there are species specific findings as the time course of degeneration in animal models is unlikely to be the same as in the human condition, and thus cannot provide precise information that would help inform surgical intervention and the timing for adjuvant therapy. We are working to provide novel data about the morphologic changes at the human motor endplate and ensuing degeneration at the neuromuscular junction following traumatic nerve injury.
