Regulation of Schwann Cell Mitochondria Homeostasis in Painful Peripheral Neuropathy

项目总结

PROJECT SUMMARY Peripheral neuropathies have heterogeneous etiologies and can emerge from traumatic, metabolic and chemotherapy induced events. Neuropathic pain is a major symptom of peripheral neuropathies, which is characterized by spontaneous pain, burning and paresthesia. Often it is associated with devastating losses of quality of life. Currently, treatments are limited and burden patients with side effects and addiction. Identifying novel strategies for pain treatment addresses a substantial unmet medical need. Research in mechanisms of painful peripheral neuropathy (PPN) has largely focused on sensory neurons, however, peripheral glia, Schwann cells (SCs), emerge as an essential component of the functional unit with sensory neurons that regulate pain states. Yet, mechanisms underlying SC contributions to PPN are largely unknown. Mitochondria dysregulation in neurons has been identified as a mechanism associated with PPN. Although, two studies show that genetic deletion of a key mitochondrial protein elicits a progressive demyelinating neuropathy, there are no studies linking a SC repair receptor signaling pathway (which could be targeted therapeutically) with mitochondria heterogeneities and/or homeostasis in SCs, relevant to neuropathic pain. We identified the low-density lipoprotein receptor related protein (LRP1) as a key SC repair receptor after injury. An important property of LRP1 is its ability to regulate lipid metabolism and glucose homeostasis, and therefore, control cellular bioenergetics. We propose that LRP1 directly regulates mitochondrial dynamics and function in SCs to optimize bioenergetic homeostasis in peripheral nerves. Our prior work investigating SC LRP1 in neuroinflammation and pain, and exciting new preliminary data showing LRP1 regulation of mitochondria numbers in the SC cytoplasm of myelinated fibers, uniquely positions us to test this hypothesis. In Aim 1, we will examine regulation of SC mitochondrial heterogeneities and bioenergetics. We propose analyses in whole nerve lysates and isolated primary SC cultures (mSC) from transgenic mice in which LRP1 is conditionally deleted from SCs (scLRP1-/-). We plan to challenge mSC metabolism with an innovative LRP1 activator, currently in phase II clinical trials. We also will test how LRP1 regulated SC mitochondria respond to stress by treatment with a chemotherapy agent known to induce PPN. In Aim 2, we will identify the mitochondrial proteome by using an unbiased proteomics screen from neuropathic and naive SCs isolated from scLRP1-/- and scLRP1+/+, respectively. We then build on the protein blueprint of how conditional deletion of LRP1 in SCs triggers PPN and apply global untargeted metabolomics to identify key metabolite changes. These studies will reveal entirely new information about mitochondria dynamics, content, and metabolism of SCs related to PPN.