Effect of mutations in TrkA gene found in insensitivity to congenital pain on cell signaling pathways

• Grant number: 18/07201-5
• Support type: Scholarships in Brazil - Master
• Effective date (Start): October 01, 2018
• Effective date (End): May 31, 2020
• Field of knowledge: Biological Sciences - Biochemistry
• Cooperation agreement: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: Deborah Schechtman
• Grantee: Beatriz Caroline de Moraes
• Home Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Congenital insensitivity to pain and anhidrosis (CIPA) is an autosomal recessive genetic disorder reported in several countries. It is characterized by recurrent episodes of unexplained fever, anhidrosis (absence of sweating), mental retardation and mainly by the lack of perception of sensory pain and absence of nociceptive and sympathetic nerves. One of the major factors leading to disease are mutations that cause loss of tropomyosin kinase A (TrkA) receptor function. TrkA has a high affinity receptor for NGF (neural growth factor) in its extracellular portion. The formation of the NGF / TrkA complex has not only a role in neuronal development, but also in sensitization of temperature increase and mechanical stimulation of nociceptors that results in hyperalgesia. NGF levels are elevated in various pain conditions, including arthritis, cystitis, prostatitis, and chronic headaches. Many mutations make up the spectrum of CIPA mutations, including those found in the kinase domain, which will be the study target of this project, since they may alter the kinase function and thus interfere with important cellular signaling pathways mediated by TrkA (PLC, PI3K and Erk). Thus, CIPA may serve as a valuable human model for determining survival and maintenance mechanisms of NGF-dependent neurons as well as their contribution to cell physiology and signaling. Since CIPA causes a decrease in pain sensitivity, we aim to understand which signaling pathways are altered with these mutations. Understanding how these different TrkA signaling pathways are affected in CIPA will help us to develop new assays to track possible TrkA-specific inhibitors that may be targeted for the production of new analgesics.