Grant: Discovery Grants Program - Individual

The nervous system is a complex network of nerve cells that create a circuit that perceives sensory information and creates a response. Failure of one or more proteins in a nerve cell within this circuit may disrupt the normal nerve transmission circuit. Disruption of neural circuits have been implicated in a variety of human diseases including schizophrenia, epilepsy, autism spectrum disorder, attention-deficit hyperactivity disorder, post-traumatic stress disorder and depression. Human nerve cells are complex in their number and the number of connections they can make with other nerve cells. As such we have chosen to work with the model organism Caenorhabditis elegans, a nematode worm with a simple nervous system of only 302 nerve cells. Sensory neurons detect the environment and pass that information through neural connections to interneurons that interpret the signal and pass the information to motor neurons to create a response. In our model, a neuropeptide receptor NPR-9 is expressed in only one C. elegans interneuron. A mutation in gene npr-9 creates an animal with limited movement or foraging behaviour when it is placed on food. npr-9 mutant animals eat the same amount of food as normal animals but gain excessive fat. This suggests that a component of the nervous system is regulating fat metabolism. We have found that when NPR-9 receptor is over-expressed, the animal becomes a hyper-roamer and is unable to sense where to find food. We are using genetic and molecular techniques to understand the signaling molecules controlling NPR-9 function and learn how NPR-9 works with classical neurotransmitters and other molecules to transmit a nerve signal and create the normal behaviourial response. We are particularly interested in discovering novel proteins that function in circuit interpretation. As many of the proteins in the nervous system of C. elegans have counterparts in human systems, this research will uncover proteins that can be tested as essential for complex neural signaling and nerve cell contributions to metabolic change. A second outcome of this research is that over-activation of NPR-9 leads to an animal that doesn't feed, because it lacks the sensory cues to identify food. This finding provides an opportunity to test chemical compounds (analogues) that may over-stimulate NPR-9 equivalent proteins in disease causing parasitic nematode species and thus cause them to stop feeding and die (an anthelmintic) without harming the host. This work will also train at least 2-3 graduate students and 3-4 undergraduate students annually in classical genetics, modern molecular biology applications such as RNAseq and bioinformatics and mammalian expression assays. These are techniques that have wide applicability to numerous scientific disciplines.