CING Lectures: Discovery of Novel and Conserved...

Discovery of Novel and Conserved Nociceptive Pathways in Congenital Insensitivity to Pain

Speaker: Vanja Nagy, PhD
CeMM, Vienna (Research Center for Molecular Medicine of the Austrian Academy of Sciences, Medical University of Vienna and Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases).

Host: Dr Kleopas Kleopa, Neurology Clinic E, CING

Abstract:

Chronic pain syndromes affect about 20% of the world’s population, creating an enormous financial burden to health care systems. Non-habit forming pain therapeutics are still lacking and by understanding the molecular and cellular basis underlying various pain syndromes we can identify novel targets for therapies. Congenital insensitivity to pain (CIP) syndromes are a group of rare genetic disorders of the peripheral nervous system marked by the absence of pain perception, due to dysfunctional or absent sensory neurons. Studies of CIP syndromes have been instrumental in uncovering molecular mechanisms underlining pain perception. For example, CIP is caused by mutations in sodium channels Nav1.7 and Nav1.9, neurotrophic growth factor β (NGFβ), and its receptor, neurotrophic receptor tyrosine kinase (NTRK1). We, and others, have additionally shown mutations in methyl transferase PR-domain containing member 12 (PRDM12) to cause a type of autosomal recessive CIP syndrome. PRDM12 is a transcription factor belonging to a conserved family implicated in cell fate decisions.  PRDM12 plays an important role in the development of the neural crest in several species and plays a potential role in pathogenesis of chronic myeloid leukemia in humans. We showed that PRDM12 is a key regulator of sensory neuronal specification in Xenopus leavis and necessary for nocifensive behavior of Drosophila melanogaster. However, very little is known of the downstream targets of PRDM12 activity and of the potential role it might play in nociceptor physiology in vertebrates. We use various genetic mouse models to delineate the function of PRDM12 in pain perception, and uncover its downstream molecular targets. We find that PRDM12 is expressed in a specific subtype of nociceptors within the dorsal root ganglia, where it regulates their survival and function. We also uncover several novel downstream targets of PRDM12, previously unknown to participate in nociception. Here, we characterize homeobox protein MOX-2 (MEOX2) and its role in pain perception in a MEOX2-deficient mouse model. These studies enhance our knowledge of basic molecular mechanism underlying pain perception, as well as to provide novel research avenues for pain therapeutics. 

Vanja Nagy, PhD
Key Researcher, LBI-RUD
Adjunct PI, CeMM
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LBI-RUD 
Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases
 
Partner institutions:
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Medical University of Vienna
Children’s Cancer Research Institute
 
c/o CeMM
Lazarettgasse 14, AKH BT 25.3
1090 Vienna, Austria