Sensory neuron-skin interaction in health and disease

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The current supplemental funding application aims to extend our understanding of chemotherapy- induced peripheral neuropathy (CIPN) based on the parent grant's innovative hypothesis that neuron-skin interactions are central to this pathology. Because CIPN frequently accompanies painful symptoms in patients that start from hands and feet, my parent grant and this application are directly relevant to pain research. The supplemental aims are related to the parent grant as they share, enhance, and supplement the parent grant’s hypothesis, experimental approaches, and developed tools. Conceptually, it supplements and advances the parent grant by exploring how immune modulation and different chemotherapeutic agents influence neuron- keratinocyte interactions and by performing in-depth analyses of RNA-seq proposed in the parent grant. The first supplemental aim seeks to characterize cell-type-specific pathology to better understand neuron-keratinocyte interactions in CIPN. This involves exploring agent-specific and shared mechanisms in two chemotherapeutics, paclitaxel (parent) and bortezomib (supplement), which have a potential to identify shared and unique CIPN mechanisms, contributing to personalized strategies for prevention and treatment. Further, we aim to gain further insight into keratinocyte pathology following chemotherapeutic treatment using additional molecular and biochemical assays, supplement to parent aims. By evaluating proliferation, cytotoxicity, stress response, and cytokine/chemokine changes, we will map out the intrinsic and extrinsic changes in keratinocytes and gain a comprehensive understanding of keratinocyte’s role in CIPN etiology. The supplement aim also seeks to expand our methodological approach to include in-depth data analyses through a collaboration with Dr. Sezin, leveraging her expertise in omics data analysis within the context of skin and immune cells to identify key genes and signaling pathways that mediate altered keratinocyte-neuron interactions in CIPN. The second supplemental aim enhances the parent aim by considering potential immunological influences in CIPN pathology. This aims to elucidate how different immune states alter CIPN susceptibility, specifically focusing on the impact of different macrophage states on pain sensitivity and their effects on neuron-keratinocyte interactions. Furthermore, an in- depth omics data analysis will elucidate how macrophages modulate keratinocyte-neuron interactions in CIPN. By characterizing the global transcriptomic changes in keratinocytes and neurons under the influence of different macrophage states, we will identify potential therapeutic targets for preventing and treating painful CIPN in a more physiologically relevant human model. Overall, we aim to create a comprehensive 'pain-in-a-dish' model for peripheral pain research and to develop an innovative approach for pain phenotyping involving keratinocyte skin cells. We believe this approach will significantly contribute to pain research, extend its applicability to a spectrum of skin inflammatory conditions, lay the groundwork for future collaboration in conducting innovative pain research related to skin diseases, and expand pain research capacity.