Multifunctional Roles of the Sensory Nervous System

Acute and chronic pain syndromes affect about 20% of the worlds population, creating an urgent and expensive public health care problem. 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 with Anhidrosis (CIP/A) is a group of rare inherited peripheral nervous system disorders caused by mutations in several genes critical for sensory neuronal function. Main clinical phenotype is an absence of pain perception; however, common to many CIP/A syndromes are recurring bacterial infections, frequent bone fractures, oral osteolysis and osteomyelitis, causing severe life-threatening complications and frequent hospitalizations. To date, there has been no comprehensive study examining the full complex clinical manifestation of this disorder. In fact, our current knowledge of CIP/A syndromes is limited to the studies of the pain-sensing dysfunctions only, while all other clinical features have largely been dismissed as side effects due to an absence of protective behavior. The central guiding principle of this proposal is that most of the clinical manifestations of CIP/A syndromes, independent of causative mutation, stem from dysfunctional sensory neurons, including pain detection, immune deficiencies and skeletal indications. To test our assertions, we have generated genetic mouse models deficient in a newly discovered CIP/A-associated transcription factor, PR-domain containing member 12 (PRDM12). We will complete a multidisciplinary behavioral and cellular elucidation of sensory neural development and function, as it pertains to nociception, immune response to pathogens and bone turnover. We will construct a complete overview of the developmental-stage and stimulus-specific transcriptomes and secretomes of sensory neurons, and therefore decipher the molecular underpinnings of the entire complex clinical indices of CIP. Additionally, we will identify epigenetic mechanisms that allow for sensory neuronal multifunctionality. The outcome of this project will have implications far beyond the rare disease studied here: it will identify novel nociceptive genes as therapeutic targets for treatment of more common pain-related conditions and shed light on basic human physiology previously unexplored.

In this project we investigated the multifaceted function of a type of sensory neurons called nociceptors, specialized cells of the peripheral nervous system. There is growing evidence that nociceptors not only detect various painful stimuli but also regulate the immune responses to bacterial infections and bone homeostasis. Indeed, in rare genetic disorders called Congenital Insensitivity to Pain with Anhidrosis (CIP/A) caused by mutations in several genes critical for sensory neuronal function, patients suffer not only from an inability to detect various noxious stimuli, but are also diagnosed with recurring bacterial infections, frequent bone fractures, oral osteolysis and osteomyelitis, leading to severe life-threatening complications and frequent hospitalizations. These symptoms are all associated with absent or dysfunctional nociceptors. Recently, we and others have identified a novel CIP/A disorder that is caused by deleterious variant in a methyl transferase, PRDM12, where patients exhibit typical CIP/A symptoms. To study this disorder and further characterize the role of nociceptors we generated a number of genetic mouse models. We aimed to understand how well mice recapitulate symptoms in patients, spatial and temporal PRDM12 activity and identify novel genes regulating pain perception downstream of PRDM12. We have conducted a multidisciplinary behavioral and cellular characterization of sensory neural development and function, as it pertains to nociception, immune response to pathogens, and bone turnover. Additionally, we have constructed a complete overview of the developmental-stage PRDM12-regulated transcriptomes. Furthermore, we have identified a new gene downstream of PRDM12, MEOX2, to be expressed in nociceptors and required for proper pain perception. Finally, we have also discovered a novel deleterious variant of PRDM12 in an consanguineous Iranian family, that in addition to typical CIP/A symptoms also exhibit autism and intellectual disability, expanding the phenotype of the disorder. We found that PRDM12 is critical for nociceptor identity and function. Additionally, we elucidated a transcriptional program regulated by PRDM12, which is different in young and mature animals. Most importantly, we have discovered that PRM12 is active in adults as well, providing the basis of targeting PRDM12 activity for therapeutic purposes. It is estimated that upwards of 30% of the world's population suffers from chronic pain syndromes, at times with unknown etiology. This represents an enormous and costly public health care problem. Nevertheless, non-habit forming, non-opioid based pain therapeutics are still lacking. However, by understanding the molecular and cellular basis underlying various (rare) pain syndromes, we can discover novel and effective therapeutic targets for the treatment of more common pain-related conditions and sheds light on basic human physiology previously unexplored.