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Understanding how GPCRs integrate nutritional and hormonal signals at the hypothalamic arcuate nucleus

Primary Supervisor: Dr Caroline Gorvin, Institute of Metabolism and Systems Research

Secondary supervisor: Professor Dmitry Veprintsev (University of Nottingham)

PhD project title: Understanding how GPCRs integrate nutritional and hormonal signals at the hypothalamic arcuate nucleus

University of Registration: University of Birmingham

Project outline:

    The hypothalamic arcuate nucleus plays a critical role in many homeostatic functions including locomotion, reproduction and appetite. To regulate food intake, arcuate neurons must respond to multiple nutritional and hormonal cues from peripheral tissues, such as the pancreas and adipose tissue, to mediate a single response. G protein-coupled receptors (GPCRs), the largest family of membrane proteins, are highly expressed at arcuate neurons and mediate responses to many of these nutritional and hormonal signals. Upon stimulation, GPCRs activate signal transduction pathways to mediate cellular responses. However, there is a limited repertoire of signal proteins for GPCRs to act upon, despite their diversity of functions. Furthermore, in complex systems such as arcuate neurons, many stimulatory and inhibitory GPCRs are expressed on the same cells, and these neurons receive multiple hormonal signals. How GPCRs on arcuate neurons integrate these stimulatory cues to mediate physiological outcomes such as food intake are poorly understood.

    This PhD studentship aims to improve understanding of this complexity by investigating how hypothalamic GPCRs may interact with each other and how their signal pathways may cross-talk. Using a multidisciplinary approach including molecular, computational and biophysical techniques, combined with state-of-the-art single-molecule imaging, this studentship aims to interrogate the signalling and trafficking of hypothalamic GPCRs to discover how they interact and how their signal pathways cross-talk. The student could learn a variety of techniques to examine GPCR function including cell culture, molecular biology (e.g. cloning, mutagenesis), structural modelling, biophysical techniques (peptide interference), signalling assays (FRET, BRET, split-luciferase) and single-molecule (super-resolution) microscopy.

    Research will be performed principally in the laboratory of Dr Caroline Gorvin within the Institute of Metabolism and Systems Research at the University of Birmingham. The appointee will also undertake some studies under the supervision of Professor Dmitry Veprintsev at the University of Nottingham, who specialises in structural and biophysical characterisation of GPCRs.

    References:

    1. Gut-brain Cross-talk in Metabolic Control. Clemmensen et al, 2017. Cell, 168 (5).
    2. Distinct G protein-coupled receptor phosphorylation motifs modulate arrestin affinity and activation and global conformation. Mayer et al, 2019. Nature Communications, 10 (1).
    3. AP2σ Mutations Impair Calcium-Sensing Receptor Trafficking and Signaling, and Show an Endosomal Pathway to Spatially Direct G-Protein Selectivity. Gorvin et al, 2018. Cell Reports, 22 (4).

    BBSRC Strategic Research Priority: Understanding the Rules of Life: Neuroscience and Behaviour

      Techniques that will be undertaken during the project:

      The student could learn a variety of techniques to examine GPCR function including cell culture, molecular biology (e.g. cloning, mutagenesis), structural modelling, biophysical techniques (peptide interference), signalling assays (FRET, BRET, split-luciferase) and single-molecule (super-resolution) microscopy.

      Contact: Dr Caroline Gorvin, University of Birmingham