Sigma 2 Receptor (TMEM97): Investigating the Peripheral Role of this Novel Therapeutic Target for Pain

University Of Texas Dallas, Richardson TX

Investigators

Linked publications & trials

Abstract

PROJECT SUMMARY Chronic pain affects greater than 50 million individuals with a huge economic burden. Currently, there are few effective treatments other than opioid-based drugs and non-steroidal anti-inflammatory drugs. Many of these treatments have a high potential for abuse and/or side effects. It is necessary to discover and study novel biological targets for the treatment of acute and chronic pain. This proposal focuses on an old molecular target, the Sigma 2/transmembrane protein 97 (σ2/TMEM97) receptor, that has been linked to pain only in the last five years. The σ2/TMEM97 receptor is an endoplasmic reticulum and plasma membrane transmembrane protein with known effects in cholesterol metabolism and calcium homeostasis. Recent behavioral pharmacology studies investigated σ2/TMEM97 as a potential therapeutic target for the treatment of pain and demonstrated that σ2/TMEM97-selective ligands were able to reverse neuropathic injury-induced mechanical hypersensitivity in mice. Neither the cellular mechanisms of this effect nor the anatomical location of the effects have been identified. In fact, limited knowledge in the context of pain of the cellular properties of σ2/TMEM97 and pharmacological properties of its ligands has been a barrier to accurately interpreting pharmacological behavioral effects. To advance the previous studies on σ2/TMEM97 as a therapeutic target for pain treatment, I aim to investigate the extent to which σ2/TMEM97 plays in the processing of nociception at the behavioral, cellular, and molecular level. I will investigate the role of σ2/TMEM97 by utilizing transgenic animals to examine the difference in cellular activity and the molecular profile of σ2/TMEM97-driven nociception in the peripheral nervous system (PNS). The goal of this proposal is to 1) understand the cellular and molecular signature of σ2/TMEM97- associated behavioral nociception in chronic inflammatory pain and 2) determine whether nociceptor-specific loss of σ2/TMEM97 function results in behavioral changes associated with perturbation to the PNS. This project includes significant training opportunities in molecular biology, animal behavior, and RNA sequencing data analysis preparing the PI for an independent career in neuroscience and biomedicine.