Temporal dynamics of TrkA signaling upon activation with nerve growth factor and a platform for discovery of non-opioid analgesics.

• Grant number: 18/04032-8
• Support Opportunities: Regular Research Grants
• Start date: June 01, 2018
• End date: May 31, 2020
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Deborah Schechtman
• Grantee: Deborah Schechtman
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Physical pain can be subdivided into nociceptive and neuropathic. Nociceptive pain is due to the activation of nociceptors caused by a lesion or disease of the somatosensorial system, considered pathological pain. Both systems can lead to chronic pain, whose treatment is still a great challenge. Thus, it is necessaty to understand the signal transduction pathways that lead to pain to develop more eficient, tolerant and specific drugs. Neuronal growth fator (NGF) has a central role in the mechanisms of pain. Recent studies NGF antagonists or of the high affinity NGF receptor, Tropomyosin kinase A receptor (TrkA), a tyrosine kinase coupled receptor, were shown to be eficiente in animal models of pain, whithout producing side effects. Thus, TrkA and the pathways activated by this kinase are good targets for the development of new drugs for the treatment of pain. Mutations of TrkA in the kinase domain lead to the developmente of Congenital insensibility to pain with anhidrosis (CIPA) and a lower sensibility to pain caused by heat or peper by the Naked mole rat is due in part to a lower activity of TrkA. However, how these mutations affect TrkA and the signal transduction pathways activated by this kinase is still not well understood. In the presente project, we intend to use our expertise in kinases to study structurally TrkA and the mutations in the kinase that lead to CIPA or a decrease in pain perception. We also intend to identify substrates and characterize the dynamics of signaling pathways activated upon NGF stimulation of TrkA, and develop a cell based assay to screen for new compounds that may serve as drug leads for the development of new and more specific analgesics, that have TrkA as a target. (AU)