The role of Tmem160 at the onset of pain after nerve injury

Pain represents a state of enormous physical and psychological stress and is the most common reason for medical advice. Patients with chronic pain are exposed to great suffering. Limited therapeutic efficacy and undesirable side effects are often associated with current therapies for severe and chronic pain. According to the latest estimates, 1.5 million people are affected by chronic pain in Austria, with 50% of them reporting direct impairments in their lives. This explains the immense need for new analgesics and for the development of utterly new therapeutic approaches, which, however, depends on comprehensive basic research into pain and its various manifestations. In particular, we lack knowledge about the mechanisms underlying the onset of pain after nerve injury and how these mechanisms may differ in dependence on the sex/gender of patients. Knowledge of these differences at the molecular level would enable us to design therapies specifically tailored to distinct patient groups (i.e., women versus men). This is of high clinical relevance, since the chronicity and severity of pain differs in many aspects in these patient groups, e.g. onset (i.e. the time at which acute pain becomes chronic, pain chronification), prevalence (often higher in women), and severity (often more severe in women). With regard to these differences, it is the declared goal of our project to identify exactly those changes that occur specifically in so-called sensory nerve fibers in the peripheral nervous system (PNS) and during the transition of acute-to-chronic pain induced by nerve injury. We could recently show that a protein named Tmem160 is a novel and male-specific factor contributing to early pain after nerve injury in mice. We will conduct experiments on mice (males and females), in which Tmem160 was deleted (KO mice), and will compare obtained data to control mice (wildtype littermates). We will use an established preclinical mouse model of nerve injury to mimic clinically relevant symptoms of nerve pain (so-called neuropathic pain). Methodologically, we use high-resolution mass spectrometry to reveal dynamic changes in the compendium of proteins (the proteome) between KO and wildtype mice, between male and female mice, and at distinct time points after nerve injury. We will particularly focus on potential changes in the interaction of neurons with the immune system (neuroimmune signaling) as we could previously show that Tmem160 plays an important role in this context. This knowledge will lay the foundation for further experiments, in which we will try to alleviate nerve injury pain in mice by specifically modulating factors that we discovered to be uniquely regulated in Tmem160 KO males versus females. We anticipate that our results will - after thorough pre- and clinical validation - serve as a starting point for future therapies to prevent the transition to chronic pain after nerve injury.