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.
