PROJECT SUMMARY/ABSTRACT Chemotherapy-induced painful peripheral neuropathy (CIPPN) significantly reduces quality of life. Patients often require tapering or cessation of chemotherapy, resulting in treatment failure and poor survival. Key mechanisms include mitochondria dysfunction, oxidative stress, and sustained neuroinflammation, which lead to neuronal hypersensitivities and chronic pain. There are no satisfactory treatment or preventative therapies available. The research on CIPPN 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, despite being highly susceptible to chemotherapy toxicity, mechanisms underlying SC contributions to CIPPN are largely unknown. We discovered a key reciprocal signaling system mediated by peroxisome proliferator activated receptor gamma (PPARγ) and low-density lipoprotein receptor related protein 1 (LRP1) that regulate SC survival, bioenergetics and inflammation. We hypothesize that PPARγ and LRP1 signaling governs the metabolic homeostasis in SCs, and boosting their activity is pro-survival, anti-inflammatory, and anti-oxidative, and thereby reduces neuronal mitochondrial dysfunction and suppresses neuronal hyperexcitability induced by chemotherapeutic agents. Our hypothesis is based on published data showing that PPARγ and LRP1 agonists prevent the development of pain-related behaviors after nerve damage and compelling new preliminary data showing that PPARγ and LRP1 regulate bioenergetics and mitochondrial dynamics in SCs in response to chemotherapeutics. In Aim 1, we will examine the role of PPARγ and LRP1 in cell survival, mitochondria dynamics and heterogeneities in primary mouse SCs. We will examine ultrastructural and bioenergetic changes in nerve mitochondria in a tumor bearing oral cancer model treated with chemotherapeutics. In Aim 2, we will examine the role of SC PPARγ-LRP1 in chemotherapy-induced oxidative stress and neuroinflammation using primary mouse SCs and tumor bearing models of CIPPN. In Aim 3, we will examine the role of SC PPARg and LRP1 signaling in chemotherapy-induced changes in nociceptive behaviors, sensory neuron metabolism and hyperexcitability. We will use two chemotherapeutics: paclitaxel and oxaliplatin for generalizability. All key findings from mouse studies will be validated in human cells and tissues including SCs, nerves collected from cancer patients, and novel SC-dorsal ganglion neuron cocultures. Abuse liabilities are determined by monitoring mouse behaviors. The potential effect of SC PPARγ-LRP1 signaling on tumor’s response to chemotherapeutics will be evaluated by monitoring tumor growth and histopathology. Proposed studies will validate the role of PPARγ in CIPPN, address new cellular and molecular mechanisms of PPARγ regulation of CIPPN, and identify LRP1 as a novel target for CIPPN. Clinical relevance is predicated on recent reports demonstrating that a selective PPARγ agonist is protective against nerve degeneration and inflammation in patients with rare neurological disorders. SP16, an innovative LRP1 agonist has shown safety and tolerability in clinical trials.

PROJECT NARRATIVE Chemotherapy-induced painful peripheral neuropathy (CIPPN) often leads to treatment failure and significantly reduces quality of life. The proposal will discover and validate whether peroxisome proliferator activated receptor gamma (PPARγ) and low-density lipoprotein receptor related protein 1 (LRP1) signaling limits Schwann cell dysfunction, and thereby alleviates aberrations in neuronal bioenergetics and hyperexcitability induced by chemotherapy. A deeper understanding of molecular mechanisms of Schwann cell function, neuroprotection and repair will help develop targeted therapies to treat CIPPN.