Defining TRPV4 contribution of Schwann cells to oral cancer pain

The K23 Career Development Award will strategically prepare the recipient to become a proficient scientist with a specialization in patient-oriented translational research study design and implementation, as well as an in- depth understanding of the neurobiology of oral cancer pain mechanisms. Additionally, the award will equip the recipient with the necessary professional skills to establish an independent career in patient-oriented orofacial pain research. BACKGROUND. Patients with oral cancer experience intense and incapacitating pain caused by mechanical pressure or stretching at the cancer site. The existing approaches for pain management, which involve opioid analgesics, have been inadequate. While the exact mechanisms that trigger pressure and stretch hypersensitivity in oral cancer patients are not yet fully understood, initial research indicates that patients express a functional pressure and stretch sensitive ion channel known as transient receptor potential vanilloid subtype 4 (TRPV4) in Schwann cells (SCs) that surround the axons of primary sensory neurons. In mouse models of oral cancer pain, TRPV4 inhibition in the oral cancer has been shown to reduce mechanical nociception in the orofacial region. SPECIFIC AIMS. This proposal aims to improve our understanding of oral cancer pain mechanisms by (1) developing and validating assays of pressure and stretch sensitivity, which will provide new methods to measure previously unexplored dimensions of oral cancer pain in patients; use genetically engineered mice to test the impact of (2) TRPV4 deletion in SCs on orofacial functional pain and (3) trigeminal neuronal hyperexcitability induced by pressure and stretch on the cancer. TRAINING. The candidate will be able to attain immediate objectives by leveraging a resource-rich institutional environment and a cohesive training plan that focuses on (1) clinical research protocol development and research methodology through a combination of didactic training and hands-on experience in patient-oriented translational pain research, and (2) utilization of genetically engineered mice to investigate the underlying mechanisms of oral cancer pain induced by pressure and stretch. MENTORSHIP. The candidate will receive support from two experienced mentors, Dr. Brian Schmidt and Dr. Donna Albertson. They have a long-standing expertise in oral cancer pain, cancer biology, and neurobiology. IMPACT. Improved understanding of the peripheral TRPV4 role in oral cancer pain offers significant potential for developing TRPV4 antagonists as novel analgesics for alleviating pain in oral cancer patients. The successful fulfillment of the proposed training program will equip the candidate with the essential abilities and expertise to lead an integrated research program on orofacial pain in an academic setting that involves both patient-oriented and laboratory research. Project Number: 1K23DE034496-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Dental and Craniofacial Research (NIDCR) | Principal Investigator: Yatendra Mulpuri | Institution: NEW YORK UNIVERSITY, NEW YORK, NY | Award Amount: $162,743 | Activity Code: K23 | Study Section: National Institute of Dental and Craniofacial Research Special Grants Review Committee[DSR] View on NIH RePORTER: https://reporter.nih.gov/project-details/11033704