TransGeNo · Transposon-activated Genome-wide search for novel Nociceptors
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2020-04-20 → 2022-04-19
- EU contribution
- €212,934
- Participants
- 1
- Scheme
- MSCA-IF-EF-RI
Lines connect the coordinator with its partners.
Results in brief
Transposon-activated Genome-wide search for novel Nociceptors
Chronic pain is a prevalent and debilitating condition, affecting approximately 30% of western societies. Our existing therapeutics carry severe risks, such as addiction. There is an urgent medical need to identify novel molecular targets in the sensory nervous system, to enable development of safer and more efficacious analgesics. Molecular pain receptors, found peripheral sensory nerves, present a uniquely promising target for such novel medications. These proteins provide the opportunity to inhibit pain at the very place its signal initiates, bypassing the need to modulate the central nervous system, and this promising both enhanced safety and efficacy. Reliably identifying novel molecular targets within the approximately 20,000 coding genes of our genome presents a logistical challenge. To address this, we developed and validated a novel strategy: TAGS (Transposon Activated Genome-wide Screening). This approach involves inducing mutations at random in cells, such that they activate genes in their vicinity. This is done in millions of cells, relying on the evolutionary strategy of the law of large numbers for the random mutations to, in rare cases, accidentally activate the right gene. The cells in which this happens are isolated from the pool of millions, and the mutations are then reverse engineered to identify the correct gene. Our overall objectives were to 1) Develop the TAGS pipeline by creating a bioinformatics analysis module 2) Identify novel mechanically activated receptors 3) Identify novel receptors for the analgesic compound hydroxy-alpha-sanshool
Data: CORDIS, © European Union
Project objective
The perception of pain is crucial for our survival, enabling avoidance of harmful physical and chemical insults. Pain initiates in primary sensory neurons, which are highly variable cells innervating the skin, mucus membranes and internal organs. These neurons express combinations of receptor molecules decoding adverse mechanical, thermal and chemical stimuli. Receptor molecules sensitive to these cues decode such inputs into action potentials, which are then relayed to the central nervous system. Uncovering the identity and regulation of these sensory receptor molecules has long been of high interest to the neuroscience community. Being the first point of possible intervention in the signalling process that leads to the perception of pain, therapeutics designed to target these molecules have high promise. Many such receptors have been identified in the past decades. The thermo- and chemosensory TRP channels, intricately involved in our perception of inflammatory pain and injury-induced hypersensitivity, are at the focus of intensive investigations. The recently identified Piezo proteins have significantly advanced our understanding of how sensory nerves decode light touch and proprioception. Many receptors in this system, however, remain to be identified. Among them are mechanoreceptors of painful tactile stimuli, as well as those responsible for the tingling, numbing sensation induced by alkaloids found in Sichuan peppers. Identifying these would open new areas of pain research and provide new, promising targets for analgesic therapy. Here I will employ a new method, Transposon-Activated Genome-wide Screening (TAGS), to identify these receptors. Inspired by the process of evolution, TAGS creates random genetic mutations in vast cell populations and enlists the law of large numbers to identify the role of individual genes. In the long-term, I will broaden the scope of TAGS to enable gene discovery across multiple disciplines in biomedical sciences.
Original text from CORDIS.
Participants
- UNIVERSITY OF LEEDS · LeedsCoordinatorUnited Kingdom
Links
Data: CORDIS, © European Union