The role of keratinocytes and TRPM3 in cipn pain

The National Cancer Institute awarded The Medical College of Wisconsin, Inc., $149,190 on January 21, 2026, under the Cancer Research Manpower program (CFDA 93.398) to fund basic research investigating the role of keratinocytes and the TRPM3 ion channel in chemotherapy-induced peripheral neuropathy (CIPN) pain.

The research uses a mouse model of CIPN to examine how non-neuronal skin cells contribute to ongoing pain behaviors following paclitaxel chemotherapy exposure. In Aim 1, the investigator will inhibit keratinocytes and observe resulting pain behaviors in CIPN mice, measure spontaneous neuronal activity in dorsal root ganglion afferents ex vivo using teased fiber recordings following keratinocyte inhibition, and use patch clamp recording to measure electrophysiological properties of dorsal root ganglion neurons in a keratinocyte-neuron coculture after paclitaxel exposure. In Aim 2, the research will expose TRPM3-knockout mice to paclitaxel and conduct behavioral assays to assess pain-like behaviors, then use calcium imaging to determine whether TRPM3 is sensitized in dorsal root ganglion neurons and keratinocytes.

The period of performance runs from January 21, 2026, to July 31, 2028. Work is performed in Wauwatosa, Wisconsin. The Cancer Research Manpower program supports biomedical training opportunities for individuals pursuing careers in basic, clinical, and prevention research relevant to the National Cancer Program.

Abstract

Individuals on chemotherapy often face debilitating side effects, including chemotherapy induced peripheral neuropathy (cipn). Up to 60-90% of patients with cancer on paclitaxel (PTX), report signs of cipn; these symptoms include both mechanically evoked and spontaneous, ongoing pain. Although much of the previous literature on cipn has focused on the dorsal root ganglion (DRG) neurons we have recently shown that non- neuronal cells of the skin epidermis, keratinocytes, also contribute to cipn-induced mechanical pain. Compared to mechanical pain, almost nothing is known about the causes of ongoing pain, and nothing is known about the contribution of keratinocytes to non-evoked, ongoing pain. My preliminary data suggests that after PTX administration, mice display non-evoked pain behaviors. Additionally, my analysis of single cell sequencing of mouse hind paws following PTX treatment revealed a potential role of TRPM3. Here, i propose to investigate the role of keratinocytes, and TRPM3, in pain behaviors using a mouse model of cipn. In aim 1, i hypothesize that keratinocytes contribute to ongoing pain behaviors in cipn mice. I plan to test this hypothesis by observing ongoing pain behaviors in mice after inhibition of keratinocytes (1A). Then i plan to utilize a method to measure spontaneous activity of DRG neuron afferents of cipn mice EX vivo following keratinocyte inhibition using teased fiber recordings (1B). In 1C, i will use a coculture of keratinocytes and DRG neurons to measure electrophysiological properties of DRG neurons following PTX exposure using patch clamp recording. In aim 2, i hypothesize that the TRPM3 channel contributes to pain behaviors in cipn. I will test this hypothesis by exposing TRPM3-/- knockout mice to PTX and use a battery of behavioral assays to assess pain-like behaviors (2A). I will use calcium imaging to determine if TRPM3 is sensitized in DRG neurons and in keratinocytes (2B). Finally, i will test whether TRPM3-/- knockout mice DRG neurons display spontaneous activity following cipn using patch clamp electrophysiology (2C). These aims will provide insights into the mechanisms of ongoing pain and will interrogate a potential target to alleviate paclitaxel induced cipn pain.