Prof S Luckman, Prof R Lucas
No more applications being accepted
Competition Funded PhD Project (European/UK Students Only)
About the Project
Obesity and type 2 diabetes are characterised by systemic insulin resistance, whereby the hormone loses its ability to reduce hepatic glucose production (HGP) and increase glucose uptake by muscle and fat. Interestingly, insulin also modulates glucose homeostasis by acting in the brain. Thus, insulin acts via Agrp- and Pomc-containing neurones in the hypothalamus to affect insulin secretion and HGP via descending pathways to the brainstem, which engage the autonomic nervous system. However, further regulation may occur through short-loop feedback involving vago-vagal reflexes. Thus, vagal afferents from the gut and pancreas project to the nucleus of the tractus solitarius (NTS) in the caudal brainstem. In turn, NTS neurones directly or indirectly modulate the output of parasympathetic preganglionic neurones in the motor nucleus of the vagus, creating a short feedback loop to control peripheral organs. The NTS is a complex structure containing a number of different neurone types. We have shown that some of these neurones respond to different physiological and pathophysiological stimuli. For example, we have shown that PrRP, but not GLP-1 neurones respond to nutrients in the GI tract to mediate the effects of gut/vagal signalling to reduce food intake, and perhaps also to regulate post-prandial glucose levels. Furthermore, currently unidentified NTS neurones are also responsive directly to circulating nutrients (glucose and amino acids) and hormones (such as insulin and leptin). Using a series of transgenic mice expressing cell-specific cre recombinase we will phenotype different populations of NTS neurone anatomically (by crossing with “Brainbow” mice to examine the connectivity of specific cells) and transcriptionally (by FACS sorting cells from EYFP reporter crosses, followed by RNA Sequencing). We will assess the ability of different NTS neurones to integrate circulating nutrients and hormones with signalling from the GI tract. We will record their electrical activity, using electrophysiology, and then modulate this activity using the latest chemogenetic and optogenetic tools. Thus, we will transduce the neurones with designer receptors or light-sensitive channels. We will then use either systemic injection of designer drugs or fibre-optic delivery of light to the neurones in order to activate or inhibit specific cell populations in vivo. In this way we aim to modify parasympathetic regulation of HGP, insulin secretion and glucose uptake. The project will make use of the experience of Professor Luckman in whole-animal metabolic research and of Professor Lucas with his experience with the Brainbow technology and in the development of new chemogenetic and optogenetic tools.
Entry Requirements
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.
Funding Notes
This project is to be funded under the MRC Doctoral Training Partnership. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the MRC DTP website www.manchester.ac.uk/mrcdtpstudentships
As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.
References
Ruud et al., 2017, Neuronal control of peripheral insulin sensitivity and glucose metabolism. Nature Comm. 8: 15259.
Cheung et al., 2009, Intestinal cholecystokinin controls glucose production through a neuronal network. Cell Metab. 10: 99-109.
Lamy et al., Hypoglycaemia-activated GLUT2 neurons of the nucleus tractus solitarius stimulate vagal activity and glucagon secretion. Cell Metab. 19: 527-538.
Dodd et al., 2014, The thermogenic effect of leptin is dependent on a distinct population of prolactin-releasing peptide (PrRP) neurons in the dorsomedial hypothalamus. Cell Metab. 20: 639-649.